6-(1H-azol-1-ylmethyl)-1-(pyrimidinyloxy)-1H benzotriazoles

ABSTRACT

(1H-azol-1-ylmethyl)substituted benzotriazole derivatives, compositions containing the same, and methods of treating estrogen dependent disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 415,440, filedSept. 28, 1989, now U.S. Pat. No. 4,943,574 which was a continuation ofapplication Ser. No. 223,486, filed on July 25, 1988, now abandoned,which was a continuation-in-part of application Ser. No. 194,775, filedon May 17, 1988, now abandoned, which was a continuation-in-part ofapplication Ser. No. 56,021, filed on June 1, 1987, now abandoned.

BACKGROUND OF THE INVENTION

A large number of azole derivatives are known in the art as antifungalagents. Recently miconazole, clotrimazole and ketoconazole, members of aclass of imidazole agents with a broad spectrum activity against avariety of yeasts, dermatophytes and dimorphous fungi, have beenreported to inhibit the action of the enzyme aromatase in BiochemicalPharmacology, 34, 1087 (1985).

Related azole derivatives have been described in U.S. Pat. Nos.4,602,025 and 4,609,666 and in the Published European patent application0,165,781 as aromatase inhibitors useful for treating estrogen dependentdiseases.

In U.S. Pat. No. 4,410,539 there are further described a number of(1H-imidazol-1-ylmethyl) substituted indole derivatives which compoundsare useful as thromboxane synthetase inhibitors.

The compounds of the present invention differ therefrom by the fact thatthey contain invariably a benzotriazole moiety and by their capabilityto inhibit the action of the enzyme aromatase. The compounds of thepresent invention are therefore useful in therapeutically treating andpreventing estrogen hormone dependent disorders in mammals.

DESCRIPTION OF THE INVENTION

The present invention is concerned with benzotriazole derivatives offormula ##STR1## the pharmaceutically acceptable acid addition salts andstereoisomeric forms thereof, wherein

A¹ ═A² --A³ ═A⁴ is a bivalent radical having the formula

    --CH═N--CH═CH--                                    (a-1),

    --CH═N--CH═N--                                     (a-2),

    or

    --CH═N--N═CH--                                     (a-3);

R is hydrogen or C₁₋₆ alkyl;

R¹ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, Ar¹, Ar² --C₁₋₆ alkyl,C₂₋₆ alkenyl or C₂₋₆ alkynyl;

R² is hydrogen; C₁₋₁₀ alkyl optionally substituted with Ar¹, C₃₋₇cycloalkyl, hydroxy or C₁₋₆ alkyloxy; Ar¹ ; C₂₋₆ alkenyl; C₂₋₆ alkynyl;C₃₋₇ cycloalkyl; bicyclo[2.2.1]heptan-2-yl; 2,3-dihydro-1H-indenyl;1,2,3,4-tetrahydronaphthalenyl; hydroxy; C₂₋₆ alkenyloxy optionallysubstituted with Ar² ; C₂₋₆ alkynyloxy; pyrimidinyloxy; di(Ar²)methoxy;(1-C₁₋₄ alkyl-4-piperidinyl)oxy; or C₁₋₁₀ alkyloxy optionallysubstituted with halo, hydroxy, C₁₋₆ alkyloxy, amino, mono, and di(C₁₋₆alkyl)amino, trifluoromethyl, carboxyl, C₁₋₆ alkyloxycarbonyl, Ar¹, Ar²--O--, Ar² --S--, C₃₋₇ cycloalkyl, 2,3-dihydro-1,4-benzodioxinyl,1H-benzimidazolyl, C₁₋₄ alkyl substituted 1H-benzimidazolyl,(1,1'-biphenyl)-4-yl

R³ is hydrogen, nitro, amino, mono- and di(C₁₋₆ alkyl)amino, halo, C₁₋₆alkyl, hydroxy or C₁₋₆ alkyloxy;

wherein Ar¹ is phenyl, substituted phenylm, naphthalenyl, pyridinyl,aminopyridinyl, imidazolyl, triazolyl, thienyl, halothienyl, furanyl,C₁₋₆ alkylfuranyl, halofuranyl or thiazolyl; and

Ar² is phenyl, substituted phenyl or pyridinyl, said substituted phenylbeing phenyl substituted with up to 3 substituents each independentlyselected from halo, hydroxy, hydroxymethyl, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy, C₁₋₆ alkyloxycarbonyl, carboxyl, formyl,(hydroxyimino)methyl, cyano, amino, mono- and di(C₁₋₆ alkyl)amino andnitro;

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo; the term "C₁₋₆ alkyl" is meant to includestraight and branch chained saturated hydrocarbon radicals having from 1to 6 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and thelike; "C₁₋₁₀ alkyl" is meant to include C₁₋₆ alkyl radicals, as definedhereinabove, and the higher homologs thereof having from 7 to 10 carbonatoms; the term "C₃₋₇ cycloalkyl" is generic to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl. "C₂₋₆ alkenyl" defines straightand branch chained hydrocarbon radicals containing one double bond andhaving from 2 to 6 carbon atoms such as, for example, ethenyl,2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl,3-methyl-2-butenyl and the like; "C₂₋₆ alkynyl" defines straight andbranch chained hydrocarbon radicals containing one triple bond andhaving from 2 to 6 carbon atoms such as, for example, 2-propynyl,2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl and the like;and when a C₂₋₆ alkenyl or a C₂₋₆ alkynyl is substituted on aheteroatom, then the carbon atom of said C₂₋₆ alkenyl or said C₃₋₆alkynyl connected to said heteroatom preferably is saturated.

It is to be understood that the ##STR2## moiety, hereinafter refered asthe 1H-azol-1-ylmethyl moiety, may be substituted on either the 4,5,6 or7 position of the benzotriazole heterocyclic ring. In addition, thecompounds of formula (I) may also contain in their structure atautomeric system and consequently these compounds can be present ineach of their tautomeric forms. Also within the scope of the inventionare the compounds of formula (I) in the form of hydrates or in solventaddition forms.

An interesting group among the compounds of formula (I) comprises thosecompounds of formula (I) wherein A¹ ═A² --A³ ═A⁴ is a bivalent radicalhaving the formula (a-1).

Another interesting group among the compounds of formula (I) comprisesthose compounds of formula (I) wherein A¹ ═A² --A³ ═A⁴ is a bivalentradical having a formula (a-2) or (a-3), with (a-2) being the mostinteresting subgroup.

Preferred compounds within the present invention are those compounds offormula (I) wherein R is hydrogen or C₁₋₄ alkyl; R¹ is hydrogen; C₁₋₆alkyl optionally substituted with phenyl or substituted phenyl; C₃₋₇cycloalkyl; phenyl; substituted phenyl; pyridinyl; naphthalenyl;thienyl; furanyl; imidazolyl; triazolyl; C₂₋₆ alkenyl or C₂₋₆ alkynyl;R² is hydrogen; C₁₋₆ alkyl optionally substituted with phenyl,substituted phenyl, naphthalenyl, thienyl, furanyl, C₁₋₄ alkylfuranyl,C₃₋₇ cycloalkyl, hydroxy or C₁₋₄ alkyloxy; phenyl; substituted phenyl;C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₃₋₇ cycloalkyl; bicyclo[2.2.1]heptan-2-yl;2,3-dihydro-1H-indenyl; 1,2,3,4-tetrahydronaphthalenyl; hydroxy; C₂₋₆alkenyloxy optionally substituted with phenyl; C₂₋₆ alkynyloxy;pyrimidinyloxy; di(phenyl)methoxy; (1-C₁₋₄ alkyl-4-piperidinyl)oxy; orC₁₋₆ alkyloxy optionally substituted with halo, hydroxy, amino, mono-anddi(C₁₋₄ alkyl)amino, trifluoromethyl, carboxyl, C₁₋₆ alkyloxy-carbonyl,phenyl, substituted phenyl, thienyl, furanyl, pyridinyl, phenoxy,phenylthio, C₃₋₇ cycloalkyl, 2,3-dihydro-1,4-benzodioxinyl,1H-benzimidazolyl, C₁₋₄ alkyl substituted 1H-benzimidazolyl,(1,1'-biphenyl)-4-yl, or with 2,3-dihydro-2-oxo-1H-benzimidazolyl; andR³ is hydrogen or nitro.

Particularly preferred compounds within the present invention are thosepreferred compounds wherein the 1H-azol-1-ylmethyl moiety is substitutedon either the 5 or 6 position of the benzotriazole heterocyclic ring.

More particularly preferred compounds within the present invention arethose particularly preferred compounds wherein R is hydrogen; R¹ ishydrogen, C₁₋₆ alkyl, phenyl or substituted phenyl; and R² is hydrogen;C₃₋₇ cycloalkyl; bicyclo[2.2.1]heptan-2-yl; 2,3-dihydro-1H-indenyl;1,2,3,4-tetrahydronaphthalenyl; C₁₋₆ alkyl optionally substituted withphenyl, substituted phenyl or C₃₋₇ cycloalkyl; or C₁₋₆ alkyloxyoptionally substituted with phenoxy, phenylthio, C₃₋₇ cycloalkyl, phenylor substituted phenyl.

Especially preferred compounds within the invention are those moreparticularly preferred compounds of formula (I) wherein R¹ is phenyloptionally substituted with halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy ortrifluoromethyl; and R² is C₁₋₆ alkyl.

More especially preferred compounds within the invention are thoseespecially preferred compounds of formula (I) wherein R¹ is phenyl orhalophenyl and R² is C₁₋₄ alkyl.

The most preferred compounds within the invention are selected form thegroup consisting of6-[(1H-imidazol-1-yl)phenylmethyl]-1-methyl-1H-benzotriazole,6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1-H-benzotriazole,the pharmaceutically acceptable acid addition salts and possiblestereochemically isomeric forms thereof.

A particular subgroup of compounds of formula (I) comprises thosecompounds, preferred, particularly preferred and more particularlypreferred compounds of formula (I) wherein R² is connected to thenitrogen atom of the benzotriazole ring on a carbon atom or wherein R²is hydrogen. Said compounds of formula (I) being represented hereinafterby compounds of formula (I-b).

Another particular subgroup of compounds of formula (I) comprises thosecompounds, preferred, particularly prefrred and more particularlypreferred compounds of formula (I) wherein R² is connected to thenitrogen atom of the benzotriazole ring on an oxygen atom. Saidcompounds of formula (I) being represented hereinafter by compounds offormula (I-c).

The compounds of formula (I) can generally be prepared by N-alkylatingan azole of formula (III) or an alkali metal salt thereof with abenzotriazole of formula (II). ##STR3## W as used in the reaction of(II) with (III) and in the following reaction schemes is an appropriateleaving group such as, for example, halo, preferably chloro, bromo oriodo, a sulfonyloxy group, e.g., methylsulfonyloxy or4-methylbenzenesulfonyloxy.

The above described N-alkylation is conveniently carried out by stirringthe reactants in the presence of a suitable organic solvent such as, forexample, an aromatic hydrocarbon, e.g., benzene, methylbenzene,dimethylbenzene, and the like; a ketone, e.g., 2-propanone,4-methyl-2-pentanone and the like; an ether, e.g., 1,4-dioxane,1,1'-oxybisethane, tetrahydrofuran and the like; a polar aproticsolvent, e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA),dimethyl sulfoxide (DMSO), 1-methyl-2-pyrrolidinone, acetonitrile,hexamethylphosphor triamide (HMPT),1,3-dimethyl-3,4,-5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMEU), benzonitrile and the like; andmixtures of such solvents. Somewhat elevated temperatures may beappropriate to enhance the rate of the reaction and in some cases thereaction may even be carried out at the reflux temperature of thereaction mixture.

The addition of an appropriate base such as, for example, an alkali oran earth alkaline metal carbonate, hydrogen carbonate, hydroxide, amideor hydride, e.g., sodium hydroxide, potassium hydroxide, potassiumcarbonate, sodium hydride and the like or an organic base, such as, forexample, N,N-dimethyl-4-pyridinamine, pyridine, N,N-diethylethanamine orN-(1-methylethyl)-2-propanamine may be employed to pick up the acidwhich is liberated during the course of the reaction. In some instancesit may be advantageous to use an excess of the azole (III) or to convertit to its metal salt form, in particularly its alkali metal salt formfollowing art-known procedures such as, e.g., by treatment of the azole(III) with an alkali metal hydroxide, alkoxide, or hydride.

Compounds of formula (I) wherein A¹ ═A² --A³ ═A⁴ is a bivalent radicalof formula (a-1), said compounds being represented by formula (I-a-1),may also be prepared by reacting a benzotriazole of formula (II) with a1-protected imidazole of formula (III-a) following the N-alkylationprocedures described hereinabove for the preparation of compounds offormula (I) starting from (II) and (III). ##STR4## In (III-a) R⁴represents a protective group such as, for example, C₁₋₆ alkylcarbonyl,C₁₋₆ alkyloxycarbonyl, arylcarbonyl or a tri(C₁₋₆ alkyl)silyl group. Insome instances the reaction of (III-a) with (II) first yields a1-protected-imidazolium salt of formula (IV) which may in situ, or ifdesired, after isolating and further purifying it, be deprotected bystirring it in an aqueous basic solution. ##STR5## In (IV) W⁻ is ananion arising from an acid such as, for example, hydrochloric acid,hydrobromic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid andthe like acids.

Particular compounds of formula (I) wherein A¹ ═A² --A³ ═A⁴ is abivalent radical of formula (a-2), said compounds being represented byformula (I-a-2), can also be prepared by N-alkylation of a triazolamineof formula (III-b) with a benzotriazole of formula (II) and subsequentdeamination of the thus prepared triazolium salt of formula (V).##STR6## In (V) W⁻ is an anion arising from an acid such as, forexample, hydrochloric acid, hydrobromic acid, methanesulfonic acid,4-methylbenzenesulfonic acid and the like acids.

The N-alkylation reaction of (III-b) with (II) is carried out accordingto similar procedures as described hereinabove for the preparation of acompound of formula (I) starting from (III) and (II). The saiddeamination reaction is conveniently conducted by means of an acidicnitrite solution in the presence of an appropriate reductant.

Preferably, the said deamination reaction is conducted with an aqueoussolution of nitrous acid or of a nitrite salt in a suitable acid in thepresence of a reducing agent such as, for example, hypophosphorous acid,formic acid, at a lower temperature.

The compounds of formula (I) may also be prepared by reacting an alcoholof formula (VI) with a reagent of formula (VII), such as, for example, a1,1'-carbonylbis[1H-imidazole]. ##STR7## In (VII) X represents ##STR8##In some instances the reaction of (VI) with (VII) first yields anintermediate of formula (VIII) which may in situ or, if desired, afterisolating and further purifying it, be converted to the desired compoundof formula (I). ##STR9## Said reaction may conveniently be conducted ina suitable solvent such as, for example, an ether, e.g., 1,4-dioxane,tetrahydrofuran; a halogenated hydrocarbon, e.g., di- ortrichloromethane; a hydrocarbon, e.g., benzene, methylbenzene; a ketone,e.g., 2-propanone, 4-methyl-2-pentanone; N,N-dimethylformamide,N,N-dimethylacetamide, or mixtures of such solvents. In order to enhancethe reaction rate, it may be advantageous to heat the reaction mixture.

The compounds of formula (I) can alternatively be prepared under similarconditions as are described in the literature for the preparation ofbenzotriazoles starting from appropriate benzenediamines orhalonitrobenzene derivatives. Depending on the nature of the substituentR² in the compounds of formula (I) to be prepared, the followingprocedures may, for example, be utilized.

The compounds of formula (I) wherein R² is hydrogen; C₁₋₁₀ alkyloptionally substituted with Ar¹, C₃₋₇ cycloalkyl, hydroxy or C₁₋₆alkyloxy; Ar¹ ; C₂₋₆ alkenyl; C₂₋₆ alkynyl; C₃₋₇ cycloalkyl;bicyclo[2.2.1]heptan-2-yl; 2,3-dihydro-1H-indenyl; or1,2,3,4-tetrahydronaphthalenyl, said radical being represented byR^(2-a) and said compounds by (I-b), may be derived from anappropriately substituted diamine of formula (IX) by diazotation andsubsequent cyclization. ##STR10## Said diazotative cyclization reactioncan be carried out by stirring the diamine of formula (IX) in an acidicnitrite solution. Preferably the said reaction is conducted with anaqueous solution of nitrous acid or of a nitrite salt, e.g., sodiumnitrite in the presence of a suitable acid such as, for example,hydrochloric acid, hydrobromic acid, formic acid, acetic acid, propanoicacid and the like acids, at a low temperature.

The compounds of formula (I), wherein R² is hydroxy, said compoundsbeing represented by formula (I-c-1), can be prepared by cyclizing anappropriately substituted azole of formula (X), which in situ may beformed by reacting an intermediate of formula (XI) with hydrazine (XII)or a hydrate thereof. ##STR11## In (XI) W¹ represents an appropriateleaving group such as, for example, halo, preferably fluoro, chloro orbromo, a sulfonyloxy group, e.g., methylsulfonyloxy or4-methylbenzenesulfonyloxy, or a C₁₋₆ alkyloxy or C₁₋₆ alkylthio group.The cyclization reaction may be carried out by stirring an intermediateof formula (XI) with hydrazine in a suitable reaction-inert solvent suchas, for example, an alcohol, e.g., methanol, ethanol, 2-propanol,1-butanol and the like or an aromatic hydrocarbon, e.g., benzene,methylbenzene, dimethylbenzene and the like. Somewhat elevatedtemperatures may be appropriate to enhance the rate of the reaction andpreferably the reaction is carried out at the reflux temperature of thereaction mixture. After completion, the reaction mixture is preferablycooled and acidified with an acidic solution such as, for example, ahydrochloric acid solution.

The compounds of formula (I-c-1) can further be O-alkylated with areagent of formula (XIII) following art-known procedures, thus preparingthe corresponding compounds of formula (I-c-2) wherein R² is optionallysubstituted C₁₋₁₀ alkyloxy, optionally substituted C₂₋₆ alkenyloxy, C₂₋₆alkynyloxy, pyrimidinyloxy, di(Ar²) methoxy or (1-C₁₋₄alkyl-4-piperidinyl)oxy, the said radical being represented byO-R^(2-b). ##STR12## Said O-alkylation is conveniently conducted in asuitable reaction-inert solvent or a mixture of such solvents. Suitablereaction-inert solvents are, for example, an aromatic hydrocarbon, e.g.,benzene, methylbenzene, dimethylbenzene, and the like; a lower alkanol,e.g., methanol, ethanol, 1-butanol and the like; a polar aproticsolvent, e.g., N,-N-dimethylformamide, N,-N-dimethylacetamide,hexamethylphosphoric triamide, dimethyl sulfoxide; and the like.Preferably in the presence of an appropriate base such as, for example,an alkali or an earth alkaline metal hydride, alkoxide, hydroxide,hydrogen carbonate, carbonate or amide. It may be advantageouspreviously to convert (I-c-1) into a metal salt form thereof, preferablythe sodium salt, in the usual manner, e.g., by the reaction of (I-c-1)with a metal base such as sodium hydroxide and the like, and thereafterto use said metal salt in the reaction with (XIII).

The compounds of formula (I-b) may alternatively be prepared by reducinga compound of formula (I-c-1), thus preparing a compound of formula(I-b) wherein R² is hydrogen and, if further desired, reacting the thusobtained compound of formula (I-b-1) with a reagent R^(2-c) W (XIV),thus preparing compounds of formula (I-b-2). ##STR13## In (XIV) W hasthe previously defined meanings and R^(2-c) has the previously definedmeaning of R^(2-a), provided that it is not hydrogen. Said reductionreaction may for example be conducted by contacting the compounds offormula (I-c-1) with hydrogen in the presence of an appropriate catalystsuch as, for example, Raney-nickel, platinum, palladium, platinum(IV)oxide, and the like, in the presence of a reaction-inert organic solventsuch as, a lower alkanol, e.g. methanol, ethanol and the like. Saidreduction may alternatively be conducted by reacting the startingmaterial (I-c-1) with titanium(III) chloride or tin(II) chloride inhydrochloric acid, optionally in the presence of a reaction inertsolvent. Preferably said reduction is carried out by O-alkylating(I-c-1) with a readily oxidizeable group such as, for example, C₁₋₆alkyloxycarbonylmethyl and the like groups and stirring the thusobtained intermediates in a suitable organic solvent, e.g., dimethylsulfoxide, N,N-dimethylformamide and the like in the presence of a basesuch as, for example, an alkali or an earth alkaline metal carbonate,hydrogen carbonate, hydroxide, alkoxide or amide.

The N-alkylation reaction of (I-b-1) with (XIV) can be carried out inthe usual manner, e.g., by stirring the reactants preferably at somewhatelevated temperatures in an appropriate organic solvent such as, forexample, a polar aprotic solvent, e.g., dimethyl sulfoxide,dimethylformamide and the like in the presence of an appropriate basesuch as, for example, an alkali metal hydride, hydroxide, carbonate oramide.

The compounds of formula (I-a-1) can also be obtained by desulfuratingan intermediate of formula (XV) in the usual manner, e.g., by treatingthe latter with Raney-nickel in the presence of an alcohol, e.g.,ethanol or by treating the starting compounds with sodium nitrite in thepresence of nitric acid in an aqueous medium. ##STR14## R⁵ in (XV) isC₁₋₆ alkyl.

The compounds of formula (I) may also be converted into each otherfollowing art-known functional group transformation procedures. A numberof such procedures will be described hereinafter in more detail.

The compounds of formula (I) containing an ester group may be convertedinto the corresponding acids following art-known saponificationprocedures, e.g., by treating the starting compound with an aqueousalkaline or an aqueous acidic solution. Vice versa, the carboxylic acidgroup may be converted into the corresponding ester group followingart-known esterification procedures. For example, the carboxylic acidmay be converted into a reactive derivative which subsequently isreacted with the corresponding alkanol; or by reacting the carboxylicacid and the alkanol with a suitable reagent capable of forming esters,e.g., dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide andthe like.

Compounds of formula (I) containing a formyl group may be converted intothe corresponding oxime following art-known procedures, e.g., bytreating the starting compound with hydroxylamine or an acid additionsalt form thereof in a suitable solvent, e.g., water, a lower alkanol,an ether, in the presence of a base, e.g., an alkali metal hydroxide,carbonate or hydrogen carbonate.

Compounds of formula (I) containing an alkynyl group may be convertedinto the corresponding compounds having an alkenyl group bycatalytically hydrogenating the starting compound in a suitablereaction-inert solvent according to art-known catalytic hydrogenationprocedures. Suitable catalysts are for example palladium-on-charcoal,platinum-on-charcoal and the like.

Compounds of formula (I) wherein R³ is hydrogen may by converted intocompounds wherein R³ is nitro by stirring the starting compound in asolution of nitrous acid in the presence of an appropriate acid, e.g.,sulfuric acid, or a mixture of acetic acid and acetic acid anhydride.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxic acidaddition salt forms by treatment with appropriate acids, such as, forexample, inorganic acids, such as hydrohalic acid, e.g. hydrochloric,hydrobromic and the like, and sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.

The compounds of formula (I) containing an acidic proton may also beconverted to their therapeutically active non-toxic metal or aminesubstitution salts, by treatment with appropriate organic or inorganicbases. Conversely the metal or amine substitution salt form can beconverted into the free acidic form by treatment with an acid.

A number of intermediates and starting materials in the foregoingpreparation are known compounds which may be prepared according toart-known methodologies of preparing said or similar compounds and someintermediates are news. A number of such preparation methods will bedescribed hereinafter in more detail.

Starting materials of formula (II) can conveniently be prepared by thefollowing reaction sequence. An aldehyde or ketone of formula (XVI) isreduced with an appropriate reductant such as, for example an aluminumor boron hydride or a complex hydride, e.g., lithium aluminum hydride,sodium borohydride, yielding an alcohol of formula (XVII), and issubsequently converted into a benzotriazole of formula (VI-c-1)following the cyclization procedure described hereinabove for theconversion of (XI) to (I-c-1). If desired, the thus obtainedbenzotriazole may further be converted into an appropriate intermediateof formula (VI-c-2), (VI-b-1) or (VI-b-2) following the same proceduresas described for the conversion of (I-c-1) to (I-c-2), (I-c-1) to(I-b-1) and (I-b-1) to (I-b-2). The desired starting materials offormula (II) wherein W represents a leaving group may then be obtainedby converting the hydroxy moiety of the benzotriazoles of formulae (VI)into a reactive ester following standard procedures as known in the art.Halides are generally prepared by the reaction of (VI) with anappropriate halogenating agent such as, for example, thionyl chloride,sulfuryl chloride, pentachlorophoshorane, pentabromophoshorane,phosphoryl chloride, hydrochloric acid, hydrobromic acid and the like.When the leaving group is a iodide it is preferably prepared from thecorresponding chloride or bromide by the replacement of that halogenwith iodine. Other reactive esters such as methanesulfonates and4-methylbenzenesulfonates are obtained by the reaction of the alcoholwith an appropriate sulfonyl halide such as, for example,methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride. ##STR15##In the above reaction scheme R¹, R^(2-b) and R^(2-c) are the same aspreviously described.

In addition to the above described procedure the intermediates offormula (II), wherein R² is a radical of formula R^(2-a), may also beprepared from an appropriately substituted benzoic acid of formula(XVIII) according to the following reaction sequence. An intermediate offormula (XVIII) is reacted with an appropriate amine of formula (XIX)following art-known N-arylation procedures and is subsequently subjectedto a nitro-to-amine reduction reaction yielding an intermediate offormula (XXI). The latter is converted into a benzotriazole derivativeof formula (XXII) according to similar cyclization procedures asdescribed hereinabove for the preparation of (I-b). The carboxylic acidfunction of the benzotriazole (XXII) is then converted into thecorresponding alcohol (VI-b-3) in the usual manner, e.g. by reductionwith an appropriate reducing agent, e.g., lithium tetrahydroaluminate,in a suitable solvent, e.g. tetrahydrofuran. If further desired, anappropriate substituent R¹ may be introduced by converting thehydroxymethyl moiety of formula (VI-b-3) into a formyl moiety with asuitable oxidizing agent, e.g., manganese (IV) oxide or potassiumpermanganate, and reacting the thus obtained aldehyde (XXIII) with ametal alkyl, e.g., methyllithium, butyllithium, metal aryl, e.g.,phenyllithium, or with a complex metal alkyl or aryl in a suitablesolvent, e.g., tetrahydrofuran. The desired intermediates of formula(II-b) may then be obtained by converting the alcohol function offormula (VI-b-3) or (VI-b) into an appropriate leaving group followingstandard procedures described hereinabove. ##STR16##

The intermediates of formula (IX) can be synthesized by variousmethodologies. For example, they may be prepared by the followingsequence of reactions. An intermediate of formula (XVII) is convertedinto a reactive ester of formula (XXIV) and reacted with an 1H-azole offormula (III) following the same procedures as described hereinabove forthe preparation of (I) starting from (II) and (III), yielding anintermediate of formula (XI). The latter is reacted with an appropriateamine of formula (XIX) following art-known N-arylation procedures and issubsequently subjected to a standard nitro-to-amine reduction reactionto yield the desired starting materials of formula (IX). ##STR17## Informula (XXIV) W¹ and W have the previously described meanings. Theabove mentioned nitro-to amine reduction reactions are generally carriedout by stirring the starting compounds in a hydrogen containing mediumin the presence of a suitable amount of an appropriate catalyst such as,for example, platinium-on-charcoal, palladium-on-charcoal, Raney-nickeland the like. In addition, the reduction may also be carried out bystirring the starting compound with sodium sulfide or sodium dithionitein a suitable solvent such as, for example water, methanol, ethanol andthe like.

Intermediates of formula (XI) may also be prepared by nitration of aintermediate of formula (XXVI). The nitration reaction is convenientlyconducted in a suitable solvent such as, for example, a halogenatedhydrocarbon, e.g., trichloromethane and the like in the presence of anappropriate acid, such as, for example, sulfuric acid, or a mixture ofacetic acid and acetic acid anhydride. ##STR18##

Intermediates of formula (XV-a) can be prepared by stirring and heatingan appropriate isothiocyanate (XXVIII), wherein R⁶ is C₁₋₆ alkyl or Ar²--C₁₋₆ alkyl, with an appropriately substituted amine (XXVII) in thepresence of a suitable reaction-inert organic solvent such as, forexample, a halogenated hydrocarbon, e.g., dichloromethane; subsequentlyby converting the thus obtained thiourea (XXIV) to the correspondingcarbamimidothioate (XXXI) with a halogenide (XXX), wherein R⁵ is C₁₋₆alkyl and Halo is preferably chloro, bromo or iodo, by stirring thereactants in the presence of an appropriate reaction-inert solvent,e.g., propanone; cyclizing the thus obtained carbamimidothioate (XXXI)by stirring and heating the latter in an aqueous acidic solvent, e.g.,in aqueous sulfuric acid; and finally condensing the benzotriazolemoiety following the cyclizing procedures described hereinabove.##STR19## In all of the foregoing preparations, the reaction productsmay be isolated from the reaction mixture and, if necessary, furtherpurified according to methodologies generally known in the art.

Starting materials and intermediates used in all of the precedingprocedures for which no specific preparations are given herein, aregenerally known and/or may all be prepared following art-knownmethodologies described in the literature for the preparation of similarknown compounds.

The compounds of formula (I) and some of the intermediates in thisinvention may have an asymmetric carbon atom in their structure. Thischiral center may be present in a R-- and a S--configuration, this R--and S--notation being in correspondence with the rules described by R.S. Cahn, C. Ingold and V. Prelog in Angew. Chem., Int. Ed. Engl.,5,385,511 (1966).

The compounds of formula (I) containing an alkene moiety may be presentin a "E" or "Z" form, said E-- and Z--notation having the meaningsdescribed in J. Org. Chem., 35, 2849-2868 (1970).

Pure stereochemically isomeric forms of the compounds of this inventionmay be obtained by the application of art-known procedures.Diastereoisomers may be separated by physical separation methods such asselective crystallization and chromatographic techniques, e.g., countercurrent distribution, and enantiomers may be separated from each otherby the selective crystallization of their diastereomeric salts withoptically active acids. They may also be derived from the correspondingpure stereochemically isomeric forms of the appropriate startingmaterials, provided that the reaction occurs stereospecifically.

The compounds of formula (I), the pharmaceutically acceptableacid-addition salts and possible stereochemically isomeric forms thereofhave very interesting pharmacological properties. They inhibit theaction of the enzyme aromatase which catalyses the formation ofestrogens from androgenic steroids in mammals.

As generally accepted, estrogens are synthesized from androgens by theloss of the C-19 angular methyl group and the formation of the aromaticA ring. These reactions require NADPH and the enzyme aromatase. Theinhibition of estrogen formation from androstenedione and testosteronecan be demonstrated by in vitro-tests or in vivo-tests in mammals suchas dogs, rats, mice and cats. The in vitro-inhibition of the aromataseactivity can, for example, be demonstrated by analyzing the effects ofthe compounds of the present invention on the conversion of [1,2³H]-androstenedione or [4¹⁴ C]-androstenedione into estrone and estradiolin the presence of human placental microsomes. The in vivo-inhibition ofthe aromatase activity can, for example, be demonstrated by measuringthe suppression of the plasma estrogen concentration in female rats. The"In vitro-inhibition of the aromatase activity"-test and the "Invivo-inhibition of the aromatase activity"-test described hereinafterillustrate the estrogen inhibiting properties of the compounds offormula (I) and are based on the above principles.

In view of their capability to inhibit the biosynthesis of estrogens thesubject compounds can be used in the treatment of estrogen dependentdisorders such as, for example, breast cancer, endometriosis,endometrial cancer, polycystic ovarian disease, benign breast disease,gynecomastia, leyomyoma and the like.

The beneficial effect of aromatase inhibitors and/or anti estrogens inthese disorders, especially in the treatment of breast cancer, isdescribed in e.g. Cancer Research, 42, Suppl. 8: 3261s (1982).

The anti-tumour activity, especially in estrogen-dependent tumours, mayin vivo be demonstrated, for example, by DMBA induced Mamma tumours infemale Sprague-Dawley-rats.

In view of the usefulness of the subject compounds in the treatment ofestrogen dependent disorders it is evident that the present inventionprovides a method of treating mammals suffering from said estrogendependent disorders. Said method comprises the systemic administrationto the latter of an amount, effective to treat estrogen dependentdisorders, of a compound of formula (I), a pharmaceutically acceptableacid-addition salt, or a possible stereochemically isomeric formthereof. In particular there is provided a method of inhibiting estrogensynthesis in mammals which comprises the systemic administration to saidmammals of an estrogen synthesis inhibitory amount, more particularly anaromatase inhibitory amount, of a compound of formula (I).

In addition to the above, some compounds of formula (I) show aninhibitory action or the biosynthesis of thromboxane A₂.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions: orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not cause a significantdeletorious effect to the skin. Said additives may facilitate theadministration to the skin and/or may be helpful for preparing thedesired compositions. These compositions may be administered in variousways, e.g., as a transdermal patch, as a spot-on, as an ointment.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

Those of skill in treating the estrogen dependent disorders could easilydetermine the effective amount from the test results presentedhereinafter. In general it is contemplated that an effective amountwould be from 0.0001 mg/kg to 10 mg/kg body weight, and more preferablyfrom 0.001 mg/kg to 0.5 mg/kg body weight.

The following examples are intended to illustrate and not to limite thescope of the invention. Unless otherwise stated all parts therein are byweight.

EXPERIMENTAL PART A. Preparation of Intermediates Example 1

a) A solution of 14 parts of (4-chloro-3-nitrophenyl)(4-fluorophenyl)-methanone in 69 parts of 2-propanamine was stirredovernight at reflux temperature. The reaction mixture was poured intowater. The precipitate was filtered off and washed with water, dried,filtered and evaporated, yielding 14.7 parts (97.2%) of (4-fluorophenyl)[4-[(1-methylethyl)-amino]-3-nitrophenyl]methanone as a residue (int.1).

b) A solution of 14.7 parts of (4-fluorophenyl)[4-[(1-methylethyl)-amino]-3-nitrophenyl]methanone in 120 parts ofethanol was hydrogenated at 2.10⁵ Pa with 3 parts of Raney nickelcatalyst. After the calculated amount of hydrogen was taken up, thecatalyst was filtered off over diatomaceous earth and the filtrate wasevaporated, yielding 12.3 parts (92.1%) of[3-amino-4-[(1-methylethyl)amino]phenyl] (4-fluorophenyl)-methanone as aresidue (int. 2).

c) To a stirred and cooled (5° C.) solution of 12.3 parts of[3-amino-4-[(1-methylethyl)amino]phenyl] (4-fluorophenyl)methanone in150 parts of a hydrochloric acid solution 6N were added 4.7 parts ofsodium nitrite. Upon complete addition, stirring was continued for 1hour at room temperature. The mixture was treated with a potassiumcarbonate solution to pH 9 and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated,yielding 17 parts (100%) of (4-fluorophenyl)[1-methylethyl)-1H-benzotriazol-5-yl]methanone as a residue (int. 3).

d) To a stirred solution of 17 parts of (4fluorophenyl)[1-(1-methylethyl)-1H-benzotriazol-5-yl]methanone in 80 parts of ethanolwere added 3.4 parts of sodium tetrahydroborate. After stirring for 1hour at room temperature, the reaction mixture was neutralized to pH 7.The reaction mixture was concentrated and the product was extracted withethyl acetate. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography over silica gel using amixture of dichloromethane and methanol (98:2 by volume) as eluent. Thepure fractions were collected and the eluent was evaporated, yielding10.7 parts (62.5%) ofα-(4-fluorophenyl)-1-(1-methylethyl)-1H-benzotriazole-5-methanol as aresidue (int. 4).

In a similar manner there were also prepared:1-cyclopropyl-α-(4-fluorophenyl)-1H-benzotriazole-5-methanol as aresidue (int. 5); and1-cyclohexyl-α-(4-fluorophenyl)-1H-benzotriazole-5-methanol as a residue(int. 6).

Example 2

a) A mixture of 50 parts of 4-chloro-3-nitrobenzoic acid and 222 partsof 1-butanamine was stirred for 3 hours at reflux temperature. Aftercooling and evaporation of the excess of 1-butanamine, the reactionmixture was acidified with a sulfuric acid solution 2N to pH 1. Theprecipitated product was filtered off and dried, yielding 59 parts(100%) of 4-(butylamino)-3-nitrobenzoic acid (int. 7).

b) A mixture of 50 parts of 4-(butylamino)-3-nitrobenzoic acid and 240parts of methanol was hydrogenated in a Parr apparatus at 3.10⁵ Pa andat room temperature with 40 parts of Raney Nickel catalyst undernitrogen atmosphere. After the calculated amount of hydrogen was takenup, the catalyst was filtered off over diatomaceous earth and thefiltrate was evaporated to dry, yielding 43.7 parts (100%) of3-amino-4-(butylamino)benzoic acid; mp. 158° C. (int. 8).

c) To a stirred and cooled mixture of 43.7 parts of3-amino-4-(butylamino)benzoic acid and 200 parts of a hydrochloric acidsolution 6N was added dropwise a solution of 22 parts of sodium nitritein a small amount of water. Upon complete addition, the reaction mixturewas stirred for 4 hours at 10°-20° C. The product was filtered off,washed with 30 parts of water and crystallized from a mixture of2-propanone and ethyl acetate. The product was filtered off and dried,yielding 33.3 parts (72.6%) of 1-butyl-1H-benzotriazole-5-carboxylicacid; mp. 192.5° C. (int. 9).

d) To a stirred and cooled (0° C.) suspension of 23.1 parts of lithiumtetrahydroaluminate in 270 parts of dry tetrahydrofuran were addedportionwise 45 parts of 1-butyl-1H-benzotriazole-5-carboxylic acid. Uponcomplete addition, stirring was continued for 1 hour at 0° C. Thereaction mixture was hydrolysed with 50 parts of water. The whole wasfiltered and washed with a mixture of dichloromethane and methanol(90:10 by volume). The filtrate was evaporated to dry and the residuewas purified by column chromatography over silica gel using a mixture ofdichloromethane and methanol (98:2 by volume) as eluent. The purefractions were collected and the eluent was evaporated, yielding 18parts (42.7%) of 1-butyl-1H-benzotriazole-5-methanol as an oily residue(int. 10).

In a similar manner there were also prepared:

    ______________________________________                                         ##STR20##                                                                    Int.                                                                          No.     R.sup.2       P     base/salt                                                                              mp (°C.)                          ______________________________________                                        11      CH.sub.3      7     base     106                                      12      (CH.sub.2).sub.3CH.sub.3                                                                    7     base     residue                                  13      (CH.sub.2).sub.3CH.sub.3                                                                    6     base     residue                                  14      CH.sub.3      4     base     residue                                  15      CH.sub.3      5     base     residue                                  16      CH.sub.3      6     base     oil                                      17      (CH.sub.2).sub.3CH.sub.3                                                                    4     base     residue                                  ______________________________________                                    

In the foregoing and following tables of the experimental part "P"represents the position of the substitution on the benzene moiety of thebenzotriazole heterocycle.

Example 3

a) To a stirred mixture of 7.4 parts of potassium permanganate, 0.6parts of 2-(2-methoxyethoxy)-N,N-bis[2-(2-methoxyethoxy)ethyl]ethamamine and 130 parts of dichloromethane was added dropwise asolution of 7.6 parts of 1-methyl-1H-benzotriazole-7-methanol indichloromethane. Upon complete addition, stirring was continued for 2hours. The reaction mixture was filtered over diatomaceous earth andwashed with dichloromethane. The organic layer was washed with 30 partsof a hydrochloric acid solution 2N and then with a sodium carbonatesolution, dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture of dichloromethaneand methanol (98:2 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated, yielding 3.5 parts (46.6%) of1-methyl-1-H-benzotriazole-7-carboxaldehyde; mp. 126° C. (int. 18).

b) To a stirred and refluxed Grignard complex, previously preparedstarting from 8.15 parts of 1-bromo-3-fluorobenzene, 1.2 parts ofmagnesium and a small amount of 1,1'-oxybisethane was added a solutionof 5 parts of 1-methyl-1H-benzotriazole-7-carboxaldehyde in 80 parts of1,1'-oxybisethane. After stirring for 2 hours at room temperature, thereaction mixture was poured into 300 parts of water. The product wasextracted three times with 65 parts of dichloromethane. The combinedextracts were dried, filtered and evaporated. The residue was stirredfor 15 minutes in 100 parts of water and 13 parts of petroleum ether atroom temperature. The product was filtered off and dried, yielding 7.6parts (95.2%) ofα-(3-fluorophenyl)-1-methyl-1H-benzotriazole-7-methanol; mp. 152° C.(int. 19).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR21##                                                                    Int.                                                                          No. R.sup.1   R.sup.2   P  base/salt                                                                           mp (°C.)                              __________________________________________________________________________    20  phenyl    (CH.sub.2).sub.3CH.sub.3                                                                7  base  125° C.                               21  phenyl    CH.sub.3  7  base  residue                                      22  H.sub.3 C CH.sub.3  7  base  126° C.                               23  H.sub.3 C (CH.sub.2).sub.3CH.sub.3                                                                7  base  residue                                      24  3-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                7  base  112.0° C.                             25  4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                6  base  residue                                      26  4-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                6  base  residue                                      27  3-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                6  base  residue                                      28  3-F C.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                7  base  116° C.                               29  3-ClC.sub.6 H.sub.4                                                                     CH.sub.3  7  base  128° C.                               30  3-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                6  base  residue                                      31  3-FC.sub.6 H.sub.4                                                                      CH.sub.3  5  base  residue                                      32  CH.sub.3(CH.sub.2).sub.2                                                                CH.sub.3  5  base  residue                                      33  3-ClC.sub.6 H.sub.4                                                                     CH.sub.3  5  base  residue                                      34  3-ClC.sub.6 H.sub.4                                                                     CH.sub.3  6  base  residue                                      35  4-FC.sub.6 H.sub.4                                                                      CH.sub.3  6  base  residue                                      36  4-ClC.sub.6 H.sub.4                                                                     CH.sub.3  6  base  residue                                      37  CH.sub.3(CH.sub.2).sub.2                                                                CH.sub.3  6  base  residue                                      38  3-BrC.sub.6 H.sub.4                                                                     CH.sub.3  5  base  oil                                          39  3-FC.sub.6 H.sub.4                                                                      CH.sub.3  6  base  residue                                      40  3-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                5  base  residue                                      41  H.sub.3 C (CH.sub.2).sub.3CH.sub.3                                                                5  base  residue                                      42  H.sub.3 C CH.sub.3  6  base  residue                                      43  3-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                5  base  residue                                      44  4-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                5  base  82° C.                                45  4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                5  base  residue                                      46  4-BrC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                5  base  residue                                      47  4-ClC.sub.6 H.sub.4                                                                     CH.sub.3  5  base  residue                                      48  3-BrC.sub.6 H.sub.4                                                                     CH.sub.3  6  base  residue                                      49  4-BrC.sub.6 H.sub.4                                                                     CH.sub.3  6  base  residue                                      50  4-BrC.sub.6 H.sub.4                                                                     CH.sub.3  5  base  residue                                      51  4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.3  6  base  residue                                      52  2-ClC.sub.6 H.sub.4                                                                     CH.sub.3  6  base  residue                                      53  4-CH.sub.3C.sub.6 H.sub.4                                                               CH.sub.3  6  base  residue                                      54  2-naphthalenyl                                                                          CH.sub.3  6  base  residue                                      55  4-H.sub.3 COC.sub.6 H.sub.4                                                             CH.sub.3  6  base  residue                                      __________________________________________________________________________     and α-[     4-(4,5-dihydro-4,4-dimethyl-2-oxoazoly)phenyl]-1-methyl-1H-benzotriazole-6    -methanol as a residue (int. 56).

Example 4

a) A mixture of 36.5 parts of 1-butyl-1H-benzotriazole-5-methanol, 35parts of manganese(IV) oxide and 390 parts of dichloromethane wasstirred for 12 hours at room temperature. The manganese(IV) oxide wasfiltered off over diatomaceous earth and another portion of 35 parts ofmanganese(IV) oxide was added to the filtrate. After stirring for 12hours at room temperature, the whole was filtered and the filtrate wasevaporated. The residue was purified by column chromatography oversilica gel using dichloromethane as eluent. The pure fractions werecollected and the eluent was evaporated, yielding 15.3 parts (42.2%) of1-butyl-1H-benzotriazole-5-carboxaldehyde as a residue (int. 57).

b) To a stirred and cooled (-78° C.) solution of 7.2 parts of3-bromothiophene in 70 parts of 1,1'-oxybisethane were added 30 parts ofa 1-butyllithium solution 1.6M in hexane. After stirring for 20 minutesat this low temperature, a solution of 6 parts ofbutyl-1H-benzotriazole-5-carboxaldehyde was added to the previousmixture. The reaction mixture was stirred for 2 hours at -78˜-40° C. Thewhole was poured into 200 parts of ice water and the product wasextracted three times with 56 parts of 1,1'-oxybisethane. The combinedextracts were dried, filtered and evaporated. The residue was purifiedby column chromatography over silica gel using a mixture ofdichloromethane and methanol (98.2 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from 2,2'-oxybispropane. The product was filtered off anddried, yielding 5 parts (58.9%) of1-butyl-α-(3-thienyl)-1H-benzotriazole-5-methanol; mp. 80° C. (int. 58).

In a similar manner there were also prepared:

1-butyl-α-(2-thienyl)-1H-benzotriazole-5-methanol as a residue (int.59);

1-methyl-α-(2-thienyl)-1H-benzotriazole-6-methanol as a residue (int.60); and

1-methyl-α-(3-thienyl)-1H-benzotriazole-6-methanol as a residue (int.61).

Example 5

a) To a stirred mixture of 496 parts of aluminum chloride in 900 partsof benzene was added dropwise a solution of 256 parts of4-fluoro-3-nitrobenzoyl chloride in 225 parts of benzene at ±10° C. Uponcomplete addition, stirring was continued first for 1.5 hours in an icebath and then for 8 hours at room temperature. The mixture was heated to60° C., cooled again and poured into crushed ice and 180 parts ofconcentrated hydrochloric acid. The separated organic layer was dried,filtered and concentrated. The concentrate was dissolved in 2100 partsof 2,2'-oxybispropane, the solution was treated with diatomaceous earthand activated charcoal. After filtration, the filtrate was concentrated.The crystallized product was filtered off and dried, yielding 223 parts(73%) of (4-fluoro-3-nitrophenyl) phenylmethanone; mp. 59° C. (int. 62).

b) To a cooled (ice bath) solution of 24.5 parts of(4-fluoro-3-nitrophenyl) phenylmethanone in 120 parts of methanol wereadded portionwise 1.5 parts of sodium tetrahydroborate. Upon completeaddition, stirring was continued for 15 minutes at 0° C. A solution of 3parts of acetic acid in 25 parts of water was added dropwise to themixture. Upon completion, the mixture was concentrated. Water was addedto the residue and the product was extracted with dichloromethane. Theextract was dried, filtered and concentrated, yielding 25.1 parts (100%)of 4-fluoro-3-nitro-α-phenylbenzenemethanol as an oily residue (int.63).

c) A mixture of 25 parts of 4-fluoro-3-nitro-α-phenylbenzenemethanol, 20parts of hydrazine monohydrate and 80 parts of ethanol was stirred for1.5 hours at reflux temperature. After cooling, 20 parts of ahydrochloric acid solution 10N were added. After concentration, theresidue was washed twice with 50 parts of water and dissolved in asolution of 300 parts methanol (10%) in trichloromethane. The organiclayer was dried, filtered and concentrated, yielding 23.8 parts (98.6%)of 1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol as a residue (int.64).

d) To a stirred solution of 1.2 parts of sodium hydroxide in 40 parts ofmethanol were added 7.8 parts of1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol. After concentration, 18parts of methylbenzene were added to the concentrate. The solvent wasevaporated again and the residue was dissolved in 27 parts ofN,N-dimethylformamide. 5.52 Parts of 1-iodobutane were added at once andthe whole was stirred for 30 minutes at 50° C. After concentration, 30parts of water were added. The solidified product was filtered off,washed with water and dissolved in dichloromethane. The organic layerwas dried, filtered and evaporated. The residue was crystallized from17.5 parts of 2,2'-oxybispropane. The product was filtered off anddried, yielding 7.8 parts (87.4%) of1-butoxy-α-phenyl-1H-benzotriazole-6-methanol; mp. 89.2° C. (int. 65).

In a similar manner there were also prepared:

1-ethoxy-α-phenyl-1H-benzotriazole-6-methanol; mp. 102.5° C. (int. 66);

1-(1-methylethoxy)-α-phenyl-1H-benzotriazole-6-methanol; mp. 109.6° C.(int. 67);

1-methoxy-α-phenyl-1H-benzotriazole-6-methanol; mp. 89.4° C.; and (int.68)

α-phenyl-1-propoxy-1H-benzotriazole-6-methanol; mp. 104.1° C. (int. 69).

Example 6

a) To a stirred solution of 5.2 parts of1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol in 30 parts of dimethylsulfoxide were added 0.96 parts of a sodium hydride dispersion 50%. Thereaction mixture was stirred till no more hydrogen escapted. After theaddition of 3.34 parts of ethyl 2-bromoacetate, the whole was stirredfor 30 minutes at room temperature. 1.38 Parts of potassium carbonatewere added and stirring was continued for 3 hours at 50° C. The dimethylsulfoxide layer was evaporated and the residue was taken up in water and20 parts of a hydrochloric acid solution 1N. The product was extractedwith a mixture of trichloromethane and methanol (90:10 by volume). Theextract was dried, filtered and concentrated. The concentrate wascrystallized from 32.5 parts of dichloromethane. The product wasfiltered off and dried, yielding 3.1 parts (68.8%) ofα-phenyl-1H-benzotriazole-5-methanol; mp. 143.0° C. (int. 70).

b) A mixture of 22.5 parts of α-phenyl-1H-benzotriazole-5-methanol, 4.8parts of a sodium hydride dispersion 50% and 90 parts ofN,N-dimethylformamide was stirred till hydrogen production had ceased.After the addition of 14.2 parts of iodomethane, stirring was continuedfor 30 minutes at room temperature. The mixture was concentrated. Theconcentrate was taken up in 50 parts of water and the product wasextracted with dichloromethane. The extract was dried, filtered andconcentrated. The concentrate was purified by filtration over silica gelusing a mixture of trichloromethane and methanol (99:1 by volume) aseluent. The desired fraction was collected and the eluent wasevaporated. The two isomers were separated by crystallization from ethylacetate. The first isomer was further purified by crystallisation fromethyl acetate. The product was filtered off and dried, yielding 3 parts(12.5%) of 1-methyl-α-phenyl-1H-benzotriazole-6-methanol; mp. 145° C.(int. 71).

The other isomer was collected and crystallized three times from ethylacetate. The product was filtered off and dried, yielding 3.3 parts(13.8%) of 1-methyl-α-phenyl-1H-benzotriazole-5-methanol; mp. 129° C.(int. 72)

Example 7

To a stirred solution of 6.5 parts of1-butyl-α-(3-chlorophenyl)-1H-benzotriazole-6-methanol in 45 parts oftetrahydrofuran were added 3.7 parts of thionyl chloride at roomtemperature. After stirring for 1 hour, the reaction mixture wasconcentrated. The product was extracted with ethyl acetate. The extractwas washed with a diluted sodium hydrogen carbonate solution, dried,filtered and evaporated, yielding 6.2 parts (88.3%) of1-butyl-6-[chloro(3-chlorophenyl)methyl]-1H-benzotriazole as a residue(int. 73).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR22##                                                                    Int.                         base/                                            No.  R.sup.1   R.sup.2    P  salt mp (°C.)                             __________________________________________________________________________    74   phenyl    OCH(CH.sub.3).sub.2                                                                      6  HCl  oil                                         75   phenyl    OCH.sub.3  6  HCl  residue                                     76   phenyl    OCH.sub.2CH.sub.3                                                                        6  HCl  residue                                     77   phenyl    O(CH.sub.2).sub.2CH.sub.3                                                                6  HCl  oil                                         78   phenyl    CH.sub.3   6  base oil                                         79   phenyl    O(CH.sub.2).sub.3CH.sub.3                                                                6  HCl  oil                                         80   phenyl    CH.sub.3   5  base oil                                         81   H         (CH.sub.2).sub.3CH.sub.3                                                                 7  base residue                                     82   phenyl    (CH.sub.2).sub.3CH.sub.3                                                                 7  base residue                                     83   H         CH.sub.3   7  base residue                                     84   phenyl    CH.sub.3   7  base residue                                     85   H.sub.3 C CH.sub.3   7  base residue                                     86   H.sub.3 C (CH.sub. 2).sub.3CH.sub.3                                                                7  base residue                                     87   3-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                 7  base residue                                     88   4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                 6  base residue                                     89   H         CH.sub.3   4  base residue                                     90   4-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                 6  base residue                                     91   3-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                 6  base residue                                     92   3-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                 7  base residue                                     93   H.sub.3 C(CH.sub.2).sub.2                                                               (CH.sub.2).sub.3CH.sub.3                                                                 6  base oil                                         94   3-FC.sub.6 H.sub.4                                                                      CH.sub.3   7  base residue                                     95   3-ClC.sub.6 H.sub.4                                                                     CH.sub.3   7  base residue                                     96   3-FC.sub.6 H.sub.4                                                                      CH.sub.3   5  base residue                                     97   H.sub.3 C(CH.sub.2).sub.2                                                               CH.sub.3   5  base residue                                     98   3-ClC.sub.6 H.sub.4                                                                     CH.sub.3   5  base residue                                     99   4-FC.sub.6 H.sub.4                                                                      CH.sub.3   5  base residue                                     100  3-ClC.sub.6 H.sub.4                                                                     CH.sub.3   6  base residue                                     101  4-FC.sub.6 H.sub.4                                                                      CH.sub.3   6  base residue                                     102  4-ClC.sub.6 H.sub.4                                                                     CH.sub.3   6  base residue                                     103  H.sub.3 C(CH.sub.2).sub.2                                                               CH.sub.3   6  base residue                                     104  3-BrC.sub.6 H.sub.4                                                                     CH.sub.3   5  base residue                                     105  3-FC.sub.6 H.sub.4                                                                      CH.sub.3   6  base residue                                     106  3-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     107  H.sub.3 C (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     108  H.sub.3 C CH.sub.3   6  base residue                                     109  3-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     110  4-FC.sub.6 H.sub.4                                                                      (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     111  H         (CH.sub.2).sub.3CH.sub.3                                                                 4  base residue                                     112  4-ClC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     113  3-thienyl (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     114  4-BrC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     115  2-thienyl (CH.sub.2).sub.3CH.sub.3                                                                 5  base residue                                     116  4-ClC.sub.6 H.sub.4                                                                     CH.sub.3   5  base residue                                     117  4-FC.sub.6 H.sub.4                                                                      CH(CH.sub.3).sub.2                                                                       5  base residue                                     118  3-BrC.sub.6 H.sub.4                                                                     CH.sub.3   6  base residue                                     119  4-BrC.sub.6 H.sub.4                                                                     CH.sub.3   6  base residue                                     120  4-BrC.sub.6 H.sub.4                                                                     CH.sub.3   5  base residue                                     121  4-FC.sub.6 H.sub.4                                                       cyclopropyl                                                                        5         base       residue                                             122  4-FC.sub.6 H.sub.4                                                       cyclohexyl                                                                         5         base       residue                                             123  4-CF.sub.3C.sub.6 H.sub.4                                                               CH.sub.3   6  base residue                                     124  2-ClC.sub.6 H.sub.4                                                                     CH.sub.3   6  base residue                                     125  4-CH.sub.3C.sub.6 H.sub.4                                                               CH.sub.3   6  base residue                                     126  2-naphthalenyl                                                                          CH.sub.3   6  base residue                                     127  4-CH.sub.3 OC.sub.6 H.sub.4                                                             CH.sub.3   6  base residue                                     __________________________________________________________________________

and 6-(bromophenylmethyl)-1-methyl-1H-benzotriazole monohydrobromide(int. 128); and

6-[chloro[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]methyl]-1-methyl-1H-benzotriazoleas a residue (int. 129).

Example 8

A mixture of 245 parts ofα-(4-chlorophenyl)-1-methyl-1H-benzotriazole-6-methanol and 1500 partsof a hydrobromic acid solution in acetic acid was stirred for 2.5 hoursat 40° C. The reaction mixture was evaporated at 60° C. and the residuewas stirred in dichloromethane. After cooling to 10° C., theprecipitated product was filtered off and dried, yielding 285 parts(76.6%) of 6-[bromo(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazolemonohydrobromide (int. 130).

Example 9

a) To a stirred and cooled solution of 58.1 parts of(4-chloro-3-nitrophenyl)phenylmethanone in 240 parts of methanol wereadded portionwise 4.4 parts of sodium tetrahydroborate. Upon completeaddition, stirring was continued for 30 minutes at room temperature. Thereaction mixture was evaporated. The residue was taken up in water andthe product was extracted with dichloromethane. The extract was dried,filtered and evaporated, yielding 58 parts (99.9%) of4-chloro-3-nitro-α-phenylbenzenemethanol as a residue (int. 131).

b) A mixture of 58 parts of 4-chloro-3-nitro-α-phenylbenzenemethanol and450 parts of a hydrobromic acid solution 48% in water was stirred for 45minutes at reflux temperature. After cooling, the product was extractedwith dichloromethane. The extract was dried, filtered and evaporated,yielding 71.4 parts (99.3%) of4-(bromophenylmethyl)-1-chloro-2-nitrobenzene as a residue (int. 132).

c) A mixture of 31.9 parts of4-(bromophenylmethyl)-1-chloro-2-nitrobenzene, 49.3 parts of4-methyl-1H-imidazole and 120 parts of acetonitrile was stirred for 24hours at reflux temperature. The reaction mixture was concentrated andthe concentrate was taken up in 150 parts of water. The product wasextracted with dichloromethane. The extract was dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane, methanol and methanol,saturated with ammonia, (98:1:1 by volume) as eluent. The desiredfractions were collected and the eluent was evaporated. The residue wasconverted into the ethanedioate salt in 80 parts of 2-propanol. The saltwas filtered off, washed with 2-propanol and dried, yielding 22.8 parts(54.5%) of1-[(4-chloro-3-nitrophenyl)phenylmethyl]-4-methyl-1H-imidazoleethanediotate(1:1); mp. 105° C. (int. 133).

In a similar manner there were also prepared:

1-[(4-chloro-3-nitrophenyl)methyl]-1H-imidazole; mp. 81.7° C. (int.134);

1-[(3-chloro-4-nitrophenyl)phenylmethyl]-1H-imidazole (int. 135);

1-[(4-chloro-3-nitrophenyl)phenylmethyl]-1H-imidazole (int. 136);

1-[(4-chloro-3-nitrophenyl)methyl]-2-methyl-1H-imidazole; mp. 102° C.(int. 137);

1-[(4-chloro-3-nitrophenyl)phenylmethyl]-5-methyl-1H-imidazole; mp. 164°C. (int. 138);

1-[(3-chlorophenyl)(4-methoxy-3-nitrophenyl)methyl]-1H-imidazole as aresidue (int. 139); and

1-[(3-chloro-4-nitrophenyl)(4-chlorophenyl)methyl]-1H-imidazoleethanedioate(1:1) (int. 140).

Example 10

To a stirred solution of 10 parts of4-chloro-α-methyl-3-nitrobenzenemethanol in 90 patrs of tetrahydrofuranwere added 8 parts of 1,1'-carbonylbis[1Himidazole]. After stirring for4 hours at a reflux temperature, the tetrahydrofuran layer wasevaporated. After the addition of 90 parts of methylbenzene, thereaction mixture was stirred for 75 hours at reflux. The reactionmixture was evaporated and the residue was taken up in water. The wholewas treated with an ammonium hydroxide solution and the product wasextracted with dichloromethane. The extract was dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (95:5 by volume) as eluent. The first fraction wascollected and the eluent was evaporated. The residue was crystallizedfrom 84 parts of 1,1'-oxybisethane. The product was filtered off anddried, yeilding 4.2 parts (33.3%) of1-[1-(4-chloro-3-nitrophenyl)ethyl]-1H-imidazole (int. 141).

Example 11

A mixture of 2.52 parts of 4H-1,2,4-triazol-4-amine, 8 parts of4-chloro-3-nitrobenzenemethanol methanesulfonate(ester) and 40 parts ofacetonitrile was stirred for 3 hours at reflux temperature. Aftercooling, the product was filtered off, washed with acetonitrile anddried, yielding 9.9 parts (94%) of4-amino-1-[(4-chloro-3-nitrophenyl-methyl]-1,2,4-triazoliummethanesulfonate; mp. 163.9° C. (int. 142).

b) To a stirred solution of 8.75 parts of4-amino-1-[(4-chloro-3-nitrophenyl)methyl]-1,2,4-triazoliummethanesulfonate in 85 parts of a hydrochloric acid solution 1N wereadded 7.15 parts of phosphinic acid 50%. After cooling in ice, asolution of 3.5 parts of sodium nitrite in 15 parts of water was added.The mixture was stirred for 2 hours at room temperature. An excess ofconcentrated ammonium hydroxide was added and stirring was continued for15 minutes. The product was filtered off, washed with water, 2-propanoland 2,2'-oxybispropane and crystallized from 8 parts of 2-propanol. Theproduct was filtered off and dried, yielding 5 parts (83.8%) of1-[(4-chloro-3-nitrophenyl)methyl]-1H-1,2,4-triazole; mp. 98.9° C. (int.143).

In a similar manner there was also prepared:

1-[(4-chloro-3-nitrophenyl)phenylmethyl]-1H-1,2,4-triazole as an oilyresidue (int. 144).

Example 12

To 184 parts of cold (10° C., ice bath) concentrated sulfuric acid wereadded portionwise 75 parts of 1-[(3-methoxyphenyl)methyl]-1H-imidazolemononitrate during 1 hour. Upon complete addition, stirring wascontinued for 30 minutes at 10° C. 15 Parts ofconcentrated nitric acidwere added dropwise during 30 minutes at 15° C. Uponcompletion, thewhole was stirred for 30 minutes at 10° C. The reaction mixture waspoured into 1500 parts of crushed ice and the whole was treatedwith anammonium hydroxide solution. The product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography over silica gel using amixture of ethyl acetate, methanol and methanol, saturated with ammonia,(95:2.5:2.5 by volume) as eluent. The pure fractions were collected andthe eluent was evaporated in vacuo. The residue was stirred in 45 partsof ethyl acetate. The precipitated product was filtered off, washed with2,2'-oxybispropane and dried, yielding 28.2 parts (40.3%) of1-[(3-methoxy-4-nitrophenyl)methyl]-1H-imidazole (int. 145).

Example 13

A mixture of 8 parts of 1-[(4-chloro-3-nitrophenyl)methyl]-1H-imidazoleand 42 parts of cyclohexanamine was stirred for 2 hours at refluxtemperature. The mixture was evaporated and the residue was stirred in2,2'-oxybispropane. The precipitated product was filtered off, washedwith water and 2,2'-oxybispropane and purified by column chromatographyover silica gel using a mixture of trichloromethane and methanol (90:10by volume) as eluent. The pure fractions were collected and the eluentwas evaporated. The residue was stirred in a mixture of2,2'-oxybispropane and ethyl acetate. The product was filtered off,washed with ethyl acetate and 2,2'-oxybispropane and dried in vacuo at60° C., yielding 9.5 parts (93.8%) of H-cyclohexyl-4-(1H-imidazol-1-ylmethyl)-b 2-nitrobenzenamine; mp. 121.1°C. (int. 146).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR23##                                                                    Int.                                     base/                                No. R.sup.1  R.sup.8        R.sup.9      salt    mp (°C.)              __________________________________________________________________________    147 H        NH(CH.sub.2).sub.3CH.sub.3                                                                   NO.sub.2     base    117.5° C.             148 H        NO.sub.2       NH(CH.sub.2).sub.3CH.sub.3                                                                 base     89.1° C.             149 H        NH-cyclohexyl  NO.sub.2     base    134.7° C.             150 H        NHC.sub.6 H.sub.5                                                                            NO.sub.2     base    150.8° C.             151 H.sub.3 C                                                                              NO.sub.2       NH(CH.sub.2).sub.3CH.sub.3                                                                 HNO.sub.3 /H.sub.2 O                                                                   84.7° C.             152 phenyl   NO.sub.2       NH(CH.sub.2).sub.3CH.sub.3                                                                 base    residue                      153 phenyl   NH(CH.sub.2).sub.3CH.sub.3                                                                   NO.sub.2     base    oil                          154 phenyl   NHCH(CH.sub.3).sub.2                                                                         NO.sub.2     base    oil                          155 H        NH-cyclopropyl NO.sub.2     base    111.6° C.             156 H        NHCH(CH.sub.3).sub.2                                                                         NO.sub.2     base    101.6° C.             157 H        NH(CH.sub.2).sub.2CH.sub.3                                                                   NO.sub.2     base     98.9° C.             158 phenyl   NHCH.sub.3     NO.sub.2     base    residue                      159 H        NHCH.sub.2(4-ClC.sub.6 H.sub.4)                                                              NO.sub.2     base    124.7° C.             160 H        NH(CH.sub.2).sub.2CH(CH.sub.3).sub.3                                                         NO.sub.2     base     75.4° C.             161 H        NO.sub.2       NH(CH.sub.2).sub.2CH.sub.3                                                                 base     98.4° C.             162 H        NO.sub.2       NHCH(CH.sub.3).sub.2                                                                       base     98.3                        163 H        NO.sub.2       NH(CH.sub.2).sub.2C.sub.6 H.sub.5                                                          base    100.5                        164 H        NHCH.sub.2(4-FC.sub.6 H.sub.4)                                                               NO.sub.2     base    111.0                        165 H        NHCH.sub.2CH.sub.3                                                                           NO.sub.2     base    106.2                        166 H        NHCH.sub.2(3-FC.sub.6 H.sub.4)                                                                NO.sub.2    base     95.4                        167 H                                                                                       ##STR24##     NO.sub.2     base    residue                      168 H        NH-bicyclo[2.2.1]                                                                            NO.sub.2     base    130.7                                     heptan-2-yl                                                      169 phenyl   NH-cyclohexyl  NO.sub.2     base    residue                      170 H        NH-cyclopentyl NO.sub.2     base     81.9                        171 H        NH-1,2,3,4-tetra-                                                                            NO.sub.2     base    118.0                                     hydro-1-naphthalenyl                                             172 H        NHCH.sub.2CHCH.sub.2                                                                         NO.sub.2     base     86.4                        173 H        NO.sub.2       NHCH.sub.2C.sub.6 H.sub.5                                                                  base    residue                      174 H        NHCH.sub.2 -cyclopropyl                                                                      NO.sub.2     base    101.4                        175 H        NHCH.sub.2 -2-thienyl                                                                        NO.sub.2     base    residue                      176 H        NH(CH.sub.2).sub.3OH                                                                         NO.sub.2     base    107.0                        177 H        NHCH.sub.2C(CH.sub.3).sub.3                                                                  NO.sub.2     base    113.7                        178 H        NH(CH.sub.2).sub.2N(CH.sub.3).sub.2                                                          NO.sub.2     base    111.6                        179 H        NH-2,3-dihydro-                                                                              NO.sub.2     base    200.2                                     1 .sub.--H-inden-1-yl                                            180 4-ClC.sub.6 H.sub.4                                                                    NHCH(CH.sub.3).sub.2                                                                         NO.sub.2     (COOH).sub.2                                                                          110.9                        181 4-ClC.sub.6 H.sub.4                                                                    NH-cyclohexyl  NO.sub.2     (COOH).sub.2                                                                          114.4                        182 4-ClC.sub.6 H.sub.4                                                                    NH-phenyl      NO.sub.2     base    oil                          183 4-ClC.sub.6 H.sub.4                                                                     ##STR25##     NO.sub.2     base    residue                      184 4-ClC.sub.6 H.sub.4                                                                    NHCH.sub.2(4-ClC.sub.6 H.sub.4)                                                              NO.sub.2     base    residue                      185 4-ClC.sub.6 H.sub.4                                                                    NHCH.sub.2C.sub.6 H.sub.5                                                                    NO.sub.2     base    residue                      __________________________________________________________________________

Example 14

A mixture of 7.9 parts ofN-cyclohexyl-4-(1H-imidazol-1-ylmethyl)-2-nitrobenzenamine, 22.9 partsof sodium dithionite, 288 parts of ethanol and 240 parts of water wasstirred at room temperature. Upon complete reaction, the ethanol layerwas evaporated. The aqueous layer was diluted with a potassium carbonatesolution. The whole was extracted twice: first with dichloromethane andthen with a mixture of trichloromethane and methanol (90:10 by volume).The combined extracts were dried, filtered and evaporated. The residuewas taken up in methylbenzene and the solvent was evaporated again,yielding 7 parts (98.0%) of was evaporated again, yielding 7 parts(98.0%) of N¹ -cyclohexyl-4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamineas a residue (int. 186).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR26##                                                                    Int.                                     base/                                No. R.sup.1  R.sup.8        R.sup.9      salt mp (°C.)                 __________________________________________________________________________    187 H        NH.sub.2       NHCH.sub.3   base residue                         188 H        NH(CH.sub.2).sub.3CH.sub.3                                                                   NH.sub.2     base residue                         189 H        NH.sub.2       NH(CH.sub.2).sub.3CH.sub.3                                                                 base residue                         190 H        NH-cyclohexyl  NH.sub.2     base residue                         191 H        NHC.sub.6 H.sub.5                                                                            NH.sub.2     base residue                         192 H        NHCH.sub.2C.sub.6 H.sub.5                                                                    NH.sub.2     base residue                         193 C.sub.6 H.sub.5                                                                        NH.sub.2       NH(CH.sub.2).sub.3CH.sub.3                                                                 base residue                         194 CH.sub.3 NH.sub.2       NH(CH.sub.2).sub.3CH.sub.3                                                                 base residue                         195 C.sub.6 H.sub.5                                                                        NH(CH.sub.2).sub.3CH.sub. 3                                                                  NH.sub.2     base residue                         196 C.sub.6 H.sub.5                                                                        NHCH(CH.sub.3).sub.2                                                                         NH.sub.2     base residue                         197 H        NH-cyclopropyl NH.sub.2     base residue                         198 H        NHCH(CH.sub.3).sub.2                                                                         NH.sub.2     base residue                         199 H        NH.sub.2       NHCH.sub.2C.sub.6 H.sub.5                                                                  base residue                         200 H        NH(CH.sub.2).sub.2CH.sub.3                                                                   NH.sub.2     base residue                         201 H        NHCH.sub.2(4-ClC.sub.6 H.sub.4)                                                              NH.sub.2     base residue                         202 H        NH(CH.sub.2).sub.2CH(CH.sub.3).sub.2                                                         NH.sub.2     base residue                         203 H        NH.sub.2       NH(CH.sub.2).sub.2C.sub.6 H.sub.5                                                          base residue                         204 H        NHCH.sub.2 (4-FC.sub.6 H.sub.4)                                                              NH.sub.2     base residue                         205 H        NHCH.sub.2(3-FC.sub.6 H.sub.4)                                                               NH.sub.2     base residue                         206 H                                                                                       ##STR27##     NH.sub.2     base residue                         207 H        NH-bicyclo-[2.2.1]hept-                                                                      NH.sub.2     base residue                                      2-yl                                                             208 H        NH-cyclopentyl NH.sub.2     base residue                         209 H                                                                         1,2,3,4-tetrahydro-                                                               NH.sub.2 base           residue                                                        1-naphthalenyl                                                   210 H        NHCH.sub.2CHCH.sub.2                                                                         NH.sub.2     base residue                         211 H        NHCH.sub.2 -c-C.sub.3 H.sub.5                                                                NH.sub.2     base residue                         212 H        NH(CH.sub.2).sub.3OH                                                                         NH.sub.2     base residue                         213 4-ClC.sub.6 H.sub.4                                                                    (5-methyl-2-furanyl)-                                                                        NH.sub.2     base residue                                      methylamino                                                      214 4-ClC.sub.6 H.sub.4                                                                    NHCH.sub.2(4-ClC.sub.6 H.sub.4)                                                              NH.sub.2     base residue                         215 4-ClC.sub.6 H.sub.4                                                                    NHC.sub.3 H.sub.5 -c                                                                         NH.sub.2     base residue                         __________________________________________________________________________

Example 15

A mixture of 9 parts of2,3-dihydro-N-[5(1H-imidazol-1-ylmethyl)-2-nitrophenyl]-1H-inden-1-amine,2 parts of a solution of thiophene in methanol 4% and 200 parts ofmethanol was hydrogenated at normal pressure and at room temperaturewith 2 parts of platinum-on-charcoal catalyst 5%. After the calculatedamount of hydrogen was taken up, the catalyst was filtered off and thefiltrate was evaporated, yielding 8 parts (97.3%) of N²-(2,3-dihydro-1H-inden-1-yl)-4-(1H-imidazol-1-ylmethyl-1,2-benzenediamineas a residue (int. 216).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR28##                                                                    Int.                                   base/                                  No. R       R.sup.8        R.sup.9     salt mp (°C.)                   __________________________________________________________________________    217                                                                           phenyl      NHCH.sub.3     NH.sub.2    base residue                           218 H       NH.sub.2       NH(CH.sub.2).sub.2CH.sub.3                                                                base residue                           219 H       NH.sub.2       NHCH(CH.sub.3).sub.2                                                                      base residue                           220 H       NHCH.sub.2CH.sub.3                                                                           NH.sub.2    base residue                           221                                                                           phenyl                                                                            NH-c-C.sub.6 H.sub.11                                                                 NH.sub.2       base        residue                                222                                                                           phenyl                                                                            NH.sub.2                                                                              NHCH.sub.2C.sub.6 H.sub.5                                                                    base        residue                                223 H       NHCH.sub.2 -2-thienyl                                                                        NH.sub.2    base residue                           224 H       NHCH.sub.2C(CH.sub.3).sub.3                                                                  NH.sub.2    base residue                           225 4-ClC.sub.6 H.sub.4                                                                   NHCH(CH.sub.3).sub.2                                                                         NH.sub.2    base residue                           226 4-Cl C.sub.6 H.sub.4                                                                  NH-c-C.sub.6 H.sub.11                                                                        NH.sub.2    base residue                           227 H       NH(CH.sub.2).sub.2N(CH.sub.3).sub.2                                                          NH.sub.2    base residue                           228 4-ClC.sub.6 H.sub.4                                                                   NHC.sub.6 H.sub.5                                                                            NH.sub.2    base residue                           229 4-ClC.sub.6 H.sub.4                                                                   NH(CH.sub.2).sub.2CH(CH.sub.3).sub.2                                                         NH.sub.2    base residue                           230 4-ClC.sub.6 H.sub.4                                                                    ##STR29##     NH.sub.2    base residue                           __________________________________________________________________________

Example 16

A solution of 10 parts of6-[chloro[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl]methyl]-1-methyl-1H-benzotriazoleand 10 parts of 1H-imidazole in 80 parts of acetonitrile was stirred for4 hours at reflux temperature. The reaction mixture was evaporated andthe product was extracted with ethyl acetate. The extract was washedwith a diluted potassium carbonate solution, dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of dichloromethane and methanol (98:2 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated, yielding 7.1 parts (65.6%) of6-[[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl](1H-imidazol-1-yl)methyl]-1-methyl-1-methyl-1H-benzenotriazoleas a residue (int. 231).

B. Preparation of Final compounds Example 17

A mixture of 4 parts of5-(chlorophenylmethyl)-1-methyl-1H-benzotriazole, 5.65 parts of1H-imidazole and 20 parts of acetonitrile was stirred for 1.5 hours atreflux temperature. After concentration, 50 parts of water were addedand the product was extracted with dichloromethane. The extract wasdried, filtered and concentrated. The residue was purified by filtrationover silica gel using a mixture of trichloromethane and methanol (95:5by volume) as eluent. The pure fractions were collected and the eluentwas evaporated. The residue was converted into the nitrate salt in 45parts of tetrahydrofuran. The salt was filtered off, washed withtetrahydrofuran and dried, yielding 3.9 parts (80.2%) of5-[(1H-imidazol-1-yl)phenylmethyl]-1-methyl-1H-benzotriazolemononitrate; mp. 111.9° C. (compound 1).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR30##                                                                    Comp.                                                                         No. R.sup.1  R.sup.2      A.sup.1A.sup.2A.sup.3A.sup.4                                                              P base/salt mp (°C.)             __________________________________________________________________________    2   phenyl   OCH(CH.sub.3).sub.2                                                                        CHCHNCH     6 HNO.sub.3 103.4                       3   phenyl   OCH.sub.3    CHCHNCH     6 HNO.sub.3 93.1                        4   phenyl   OCH.sub.2CH.sub.3                                                                          CHCHNCH     6 HNO.sub.3 98.1                        5   phenyl   OCH.sub.2CH.sub.2CH.sub.3                                                                  CHCHNCH     6 HNO.sub.3 120.2                       6   phenyl   O(CH.sub.2).sub.3CH.sub.3                                                                  CHCHNCH     6 HNO.sub.3 86.0                        7   phenyl   CH.sub.3     CHCHNCH     6 (COOH).sub.2                                                                            112.6                       8   H        (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     7 base      109.7                       9   phenyl   (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     7 HCl       225.2                       10  H        CH.sub.3     CHCHNCH     7 0.5 H.sub.2 O                                                                           175.8                       11  phenyl   CH.sub.3     CHCHNCH     7 base      192.2                       12  H.sub.3 C                                                                              CH.sub.3     CHCHNCH     7 base      180.1                       13  H.sub.3 C                                                                              (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     7 (COOH).sub.2                                                                            85.8                        14  3-ClC.sub.6 H.sub.4                                                                    (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     7 (COOH).sub.2                                                                            144.3                       15  4-ClC.sub.6 H.sub.4                                                                    (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     6 (COOH).sub.2                                                                            99.4                        16  H        CH.sub.3     CHCHNCH     4 base      132.7                       17  4-FC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub. 3                                                                  CHCHNCH     6 (COOH).sub.2                                                                            91.2                        18  3-FC.sub.6 H.sub.5                                                                     (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     6 (COOH).sub.2                                                                            89.8                        19  3-FC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     7 HCl       212.0                       20  CH.sub.3(CH.sub.2).sub.2                                                               (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     6 (COOH).sub.2                                                                            124.5                       21  3-FC.sub.6 H.sub.4                                                                     CH.sub.3     CHCHNCH     7 base      182.3                       22  3-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     7 base      195.1                       23  3-ClC.sub.6 H.sub.4                                                                    (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     6 (COOH).sub.2                                                                            71.5                        24  3-FC.sub.6 H.sub.4                                                                     CH.sub.3     CHCHNCH     5 base      150.1                       25  CH.sub.3(CH.sub.2).sub.2                                                               CH.sub.3     CHCHNCH     5 base      112.4                       26  3-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     5 base      146.1                       27  4-FC.sub.6 H.sub.4                                                                     CH.sub.3     CHCHNCH     5 (COOH).sub.2                                                                            152.4                       28  3-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHChNCH     6 (COOH).sub.2                                                                            90.5                        29  4-FC.sub.6 H.sub.4                                                                     CH.sub.3     CHCHNCH     6 (COOH).sub.2                                                                            96.5                        30  4-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     6 (COOH).sub.2 /0.5 H.sub.2                                                               90.2                        31  H.sub.3 C(CH.sub.2).sub.2                                                              CH.sub.3     CHCHNCH     6 base      95.0                        32  3-BrC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     5 base      143.2                       33  3-FC.sub.6 H.sub.4                                                                     CH.sub.3     CHCHNCH     6 (COOH).sub.2                                                                            189.9                       34  3-ClC.sub.6 H.sub.4                                                                    (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 (COOH).sub.2                                                                            120.8                       35  H.sub.3 C                                                                              (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 *(1:1)    100.5                       36  H.sub.3 C                                                                              CH.sub.3     CH CHNCH    6 base      116.8                       37  3-FC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 (COOH).sub.2                                                                            131.2                       38  4-FC.sub.6 H.sub.4                                                                     (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 (COOH).sub.2                                                                            166.4                       39  H        (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     4 (COOH).sub.2                                                                            95.8                        40  4-ClC.sub.6 H.sub.4                                                                    (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 (COOH).sub.2 /0.5 H.sub.2                                                               135.7                       41  3-thienyl                                                                              (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 (COOH).sub.2                                                                            168.9                       42  4-BrC.sub.6 H.sub.4                                                                    (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 (COOH).sub.2 /0.5 H.sub.2                                                               152.9                       43  3-ClC.sub.6 H.sub.4                                                                    CH.sub.3                                                                                    ##STR31##  6 base      177.4                       44  2-thienyl                                                                              (CH.sub.2).sub.3CH.sub.3                                                                   CHCHNCH     5 (COOH).sub.2                                                                            143.5                       45  4-ClC.sub.6 H.sub. 4                                                                   CH.sub.3     NCHNCH      6 (COOH).sub.2                                                                            104.2                       46  4-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHNNCH      6 0.5 H.sub.2 O                                                                           119.8                       47  4-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     5 base      172.4                       48  4-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     6 HCl/H.sub.2 O                                                                           151.2                       49  4-FC.sub.6 H.sub.4                                                                     CH(CH.sub.3).sub.2                                                                         CHCHNCH     5 base      155.3                       50  3-BrC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     6 (COOH).sub.2 /0.5 H.sub.2                                                               107.7                       51  4-BrC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     6 (COOH).sub.2                                                                            136.2                       52  4-BrC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     5 base      180.1                       53  4-FC.sub.6 H.sub.4                                                                     c-C.sub.3 H.sub.5                                                                          CHCHNCH     5 base      94.6                        54  4-FC.sub.6 H.sub.4                                                                     c-C.sub.6 H.sub.11                                                                         CHCHNCH     5 base      157.6                       55  4-CF.sub.3C.sub.6 H.sub.4                                                              CH.sub.3     CHCHNCH     6 (COOH).sub.2 /0.5 H.sub.2                                                               89.9                        56  2-ClC.sub.6 H.sub.4                                                                    CH.sub.3     CHCHNCH     6 (COOH).sub.2 /0.5 H.sub.2                                                               132.6                       57  4-CH.sub.3C.sub.6 H.sub.4                                                              CH.sub.3     CHCHNCH     6 (COOH).sub.2 /0.5 H.sub.2                                                               140.9                       58  2-naphthalenyl                                                                         CH.sub.3     CHCHNCH     6 0.5 H.sub.2 O                                                                           148.8                       59  4-CH.sub.3 OC.sub.6 H.sub.4                                                            CH.sub.3     CHCHNCH     6 (COOH).sub.2                                                                            144.2                       60  C.sub.6 H.sub.5CH.sub.2                                                                CH.sub.3     CHCHNCH     5 base      159.9                       61  CNC.sub.6 H.sub.5                                                                      CH.sub.3     CHCHNCH     5 base      176.5                       __________________________________________________________________________     *(E)-2-butenedioate                                                      

Example 18

A mixture of 12.8 parts of6-(bromophenylmethyl)-1-methyl-1H-benzotriazole monohydrobromide, 14.8parts of 4-methyl-1H-imidazole and 80 parts of acetonitrile was stirredfor 8 hours at reflux temperature. The mixture was concentrated and theresidue was stirred in 100 parts of water. The product was extractedwith dichloromethane. The extract was dried, filtered and evaporated.The residue was purified twice by column chromatography over silica gelusing a mixture of trichloromethane and methanol (99:1 by volume) aseluent. The desired fraction was collected and the eluent wasevaporated. The residue was purified by reversed phase chromatography(HPLC) over Li Chroprep RP 18 using a mixture of methanol,tetrahydrofuran and ammonium acetate (30:5:65 by volume) as eluent. Thepure fraction was collected and the eluent was evaporated. The residuewas converted into the ethanedioate salt in tetrahydrofuran. The saltwas filtered off and dried, yielding 1.6 parts (13.5%) of1-methyl-6-[(4-methyl-1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazoleethanedioate(1:1); mp. 203.1° C. (compound 62).

Example 19

A solution of 203 parts of6-[bromo(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazolemonohydrobromide and 170 parts of 1H-imidazole in 1350 parts ofmethylbenzene was stirred for 28 hours at reflux temperature. Thereaction mixture was allowed to cool to 80° C. and then evaporated. Theoily residue was dissolved in dichloromethane. The organic layer waswashed with a diluted hydrochloric acid solution. The separated aqueouslayer was treated with a sodium hydroxide solution and extracted withdichloromethane. The combined dichloromethane layers were washed withwater, dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture of dichloromethaneand methanol (95:5 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. To the residue were added 210parts of 1,1'-oxybisethane and the whole was allowed to stand overweekend. The solid product was filtered off and dried at 50° C.,yielding 48.1 parts (29.7%) of 6-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]1-methyl-1H-benzotriazole; mp. 87.7° C. (compound 63).

Example 20

To a stirred solution of 28.4 parts of 1H-1,2,4-triazole in 135 parts ofN,N-dimethylformamide were added 11.4 parts of a sodium hydridedispersion 80% under nitrogen atmosphere. After stirring for 1 hour atroom temperature, a solution of 40 parts of6-[chloro(4-chlorophenyl)methyl]-1-methyl-1H-benzotriazole in 90 partsof N,N-dimethylformamide was added to the mixture. The whole was stirredfor 1 hour at 60° C. The reaction mixture was diluted with 50 parts ofwater and the whole was evaporated. The residue was extracted with ethylacetate. The extract was washed with water, dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of dichloromethane and methanol (99:1 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from a mixture of 2-propanoneand 1,1'-oxybisethane. The product was filtered off and dried, yielding13 parts (29.2%) of6-[(4-chlorophenyl)-(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole;mp. 178.9° C. (compound 64).

Example 21

To a stirred solution of 4.25 parts of 1H-1,2,4-triazole in 47 parts ofN,N-dimethylformamide were added 2 parts of a sodium hydride dispersion50% under nitrogen atmosphere. The whole was stirred for 10 minutes atroom temperature and a solution of 6 parts of6-[chloro(3-chlorophenyl)methyl]-1-methyl-1H-benzotriazole in 47 partsof N,N-dimethylformamide was added to the mixture. The whole was stirredfor 1 hour at 50° C. and then cooled to room temperature. The productwas extracted with ethyl acetate. The extract was dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of dichloromethane and methanol (95:5 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was converted into the ethanedioate salt in2-propanone. The salt was filtered off and crystallized from a mixtureof acetonitrile and 1,1'-oxybisethane. The product was filtered off anddried, yielding 2.8 parts (33.7%) of dried, yielding 2.8 parts (33.7%)of6-[(3-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazoleethanedioate(1:1); mp. 125.0° C. (compound 65).

Example 22

A mixture of 9.1 parts of6-(bromophenylmethyl)-1-methyl-1H-benzotriazole monohydrobromide, 10.25parts of (4-methyl-1H-imidazol-1-yl)phenylmethanone and 64 parts ofacetonitrile was stirred for 3 hours at reflux temperature. Theacetonitrile layer was evaporated and the residue was stirred overnightat room temperature in a mixture of 16.6 parts of potassium carbonateand 80 parts of water. The product was extracted with dichloromethane.The extract was dried, filtered and evaporated. The residue was purifiedby column chromatography over silica gel using a mixture oftrichloromethane and methanol (98:2 by volume) as eluent. The desiredfraction was collected and the eluent was evaporated. The residue waspurified by reversed phase chromatography (HPLC) over Li Chroprep RP 18using a mixture of methanol, tetrahydrofuran and ammonium acetate(30:5:65 by volume) as eluent. The pure fraction was collected and theeluent was evaporated. The residue was further purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (95:5 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was converted into theethanedioate salt in tetrahydrofuran. The salt was filtered off anddried in vacuo at 80° C., yielding 3.1 parts (35.8%) of1-methyl-6-[(5-methyl-1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazoleethanedioate (1:1); mp. 120.7° C. (compound 66).

EXAMPLE 23

A mixture of 8.2 parts of6-(bromophenylmethyl)-1-methyl-1H-benzotriazole monohydrobromide, 3.45parts of 4H-1,2,4-triazole-4-amine and 64 parts of acetonitrile wasstirred first for 2 hours at reflux temperature and then overnight atroom temperature. The precipitate was filtered off and the filtrate wasconcentrated, yielding4-amino-1-[(1-methyl-1H-benzotriazol-6-yl)phenylmethyl]-4H-1,2,4-triazoliumbromide. To a stirred solution of the latter, 7.3 parts of a phosphinicacid solution 50% and 7.3 parts of a hydrochloric acid solution 12N in40 parts of methanol and 20 parts of water was added dropwise a solutionof 3.45 parts of sodium nitrite in 20 parts of water. Upon completeaddition, stirring was continued for 30 minutes at room temperature. Themethanol layer was evaporated and the residue was treated with anammonium hydroxide solution. The product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified twice by column chromatography over silica gelusing a mixture of trichloromethane and methanol (98:2 by volume) aseluent. The pure fractions were collected and the eluent was evaporated.The residue was converted into the ethanedioate salt in 36 parts oftetrahydrofuran. The salt was filtered off and crystallized from 45parts of ethyl acetate. The product was filtered off and dried, yielding3.1 parts (40.7%) of1-methyl-6-[phenyl-(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazoleethanedioate(1:1); mp. 164.9° C. (compound 67).

Example 24

To a stirred and heated solution of 3.2 parts of1-methyl-α-(2-thienyl)-1H-benzotriazole-6-methanol in 45 parts oftetrahydrofuran were added 4.2 parts of 1,1'-carbonylbis[1H-imidazole]under nitrogen atmosphere. After stirring for 30 minutes at 50° C., thereaction mixture was evaporated. The product was extracted with ethylacetate. The extract was washed with a diluted sodium hydrogen carbonatesolution, dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture of dichloromethaneand methanol (98:2 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom 2-propanone. The product was filtered off and dried, yielding 1.9parts (49.5%) of6-[(1H-imidazol-1-yl)(2-thienyl)methyl]-1-methyl-1H-benzotriazole; mp.157.2° C. (compound 68). In a similar manner there were also prepared:

6-[(1H-imidazol-1-yl)(3-thienyl)methyl]-1-methyl-1H-benzotriazole; mp.160.5° C. (compound 69);

5-[bis-(1H-imidazol-1-yl)methyl]-1-butyl-1H-benzotriazole; mp. 180.1° C.(compound 70); and

5-[1-(1H-imidazol-1-yl)-2-butynyl]-1-methyl-1H-benzotriazole; mp. 155.5°C. (compound 71).

Example 25

A mixture of 1.6 parts of 4-(1H-imidazol-1-ylmethyl)-N²-phenyl-1,2-benzenediamine, 20 parts of acetic acid and 1.08 parts ofconcentrated hydrochloric acid was cooled in an ice bath at 12°-16° C. Asolution of 0.83 parts of sodium nitrite in 7 parts of water was addeddropwise. Upon complete addition, the reaction mixture was allowed toreach room temperature while stirring. The reaction mixture was pouredinto alkaline ice water and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography over silica gel firstusing a mixture of trichloromethane and methanol, saturated withammonia, (97.5:2.5 by volume) and then a mixture of ethyl acetate,methanol and methanol, saturated with ammonia (95:2.5:2.5 by volume) aseluents. The pure fractions were collected and the eluent wasevaporated. The residue was taken up in a mixture of 2-propanone and2,2'-oxybispropane. The product was filtered off, washed with2,2'-oxybispropane and dried in vacuo at 60° C., yielding 0.81 parts(49.0%) of 6-(1H-imidazol-1-ylmethyl)-1-phenyl-1H-benzotriazole; mp.110.1° C. (compound 72).

In a similar manner there were also prepared:

1-cyclohexyl-6-(1H-imidazol-1-ylmethyl)-1H-benzotriazole; mp. 109.3° C.(compound 73);

1-butyl-5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 83.6°C. (compound 74);

1-butyl-6-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazoleethanedioate(1:1); mp. 109.0° C. (compound 75);

6-[(1H-imidazol-1-yl)phenylmethyl]-1-(1-methylethyl)-1H-benzotriazoleethanedioate(1:1); mp. 123.1° C. (compound 76);

6-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]-1-phenyl-1H-benzotriazolemononitrate; mp. 166.7° C. (compound 77);

6-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]-1-(phenylethyl)-1H-benzotriazolemononitrate; mp. 160.7° C. (compound 78); and

6-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]-1-[(4-chlorophenyl)methyl]-1H-benzotriazolemononitrate; mp. 185.9° C. (compound 79).

Example 26

To a stirred and cooled (0° C.) mixture of 3.9 parts of4-(1H-imidazol-1-ylmethyl)-N² -(phenylmethyl)-1,2-benzenediamine and 9.6parts of concentrated hydrochloric acid was added dropwise a solution of1.86 parts of sodium nitrite in 8 parts of water. Upon completeaddition, stirring was continued for 10-15 minutes at this lowtemperature. The reaction mixture was allowed to reach room temperatureand poured into ice water. The whole was extracted with dichloromethane.The acid aqueous layer was treated with a concentrated ammoniumhydroxide solution while cooling and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by filtration over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wasfurther purified by column chromatography over silica gel using amixture of ethyl acetate, methanol and methanol, saturated with ammonia(95:2.5:2.5 by volume) as eluent. The pure fractions were collected andthe eluent was evaporated. The product was filtered off, washed with2,2'-oxybispropane and dried in vacuo at 50° C., yielding 1.6 parts(40.9%) of 6-(1H-imidazol-1-ylmethyl)-1-(phenylmethyl)-1H-benzotriazole;mp. 85.4° C. (compound 80).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR32##                                                                    Comp.                                                                         No. R.sup.1  R.sup.2      A.sup.1A.sup.2A.sup.3A.sup.4                                                             P base/salt                                                                            mp (°C.)                 __________________________________________________________________________    81  H        CH.sub.3     CHCHNCH    5 base   141.6                           82  CH.sub.3 CH.sub.3     CHCHNCH    5 base   147.5                           83  CH.sub.3 CH.sub.3(CH.sub.2).sub.3                                                                   CHCHNCH    5 (COOH).sub.2                                                                         108.4                           84  H        CH.sub.3     CHCHNCH    6 base   159.5                           85  H        cyclopropyl  CHCHNCH    6 base   108.4                           86  H        cyclohexyl   CHCHNCH    5 base   149.4                           87  H        (CH.sub.3).sub.2CH                                                                         CHCHNCH    6 base   188.6                           88  H        C.sub.6 H.sub.5CH.sub.2                                                                    CHCHNCH    5 base   130.5                           89  H        CH.sub.3CH.sub.2CH.sub.2                                                                   CHCHNCH    6 base   113.9                           90  phenyl   CH.sub.3     CHCHNCH    6 base   105.5                           91  H        4-ClC.sub.6 H.sub.4CH.sub.2                                                                CHCHNCH    6 base   117.6                           92  H        C.sub.6 H.sub.5CH.sub.2CH.sub.2                                                            CHCHNCH    6 base   108.5                           93  H        (CH.sub.3).sub.2CH(CH.sub.2).sub.2                                                         CHCHNCH    6 HNO.sub.3                                                                            164.3-165.6                     94  H        CH.sub.3CH.sub.2CH.sub.2                                                                   CHCHNCH    5 base    89.6                           95  H        (CH.sub.3).sub.2CH                                                                         CHCHNCH    5 base   163.0                           96  H        C.sub.6 H.sub.5CH.sub.2CH.sub.2                                                            CHCHNCH    5 base    96.6                           97  H        C.sub.6 H.sub.11CH.sub.2                                                                   CHCHNCH    6 base   108.3                           98  H        4-FC.sub.6 H.sub.4CH.sub.2                                                                 CHCHNCH    6 base   101.8                           99  H        3-FC.sub.6 H.sub.4CH.sub.2                                                                 CHCHNCH    6 base   110.0                           100 H        cycloheptyl  CHCHNCH    6 base   110.6                           101 H        CH.sub.3CH.sub.2(CH.sub.3)CH                                                               CHCHNCH    6 HNO.sub.3                                                                            165.3                           102 H        CH.sub.3CH.sub.2                                                                           CHCHNCH    6 base    96.7                           103 H        bicyclo[2.2.1]-                                                                            CHCHNCH    6 HNO.sub.3                                                                            155.5-156.7                                  hept-2-yl                                                        104 phenyl   cyclcohexyl  CHCHNCH    6 base   119.0                           105 H        1,2,3,4-tetrahy-                                                                           CHCHNCH    6 (COOH).sub.2                                                                         166.1                                        dro-1-naphtalenyl                                                106 H        CH.sub.2CHCH.sub.2                                                                         CHCHNCH    6 base   114.2                           107 H        cyclcopentyl CHCHNCH    6 H.sub.2 O                                                                            108.8-111.7                     108 H        cyclopropyl-CH.sub.2                                                                       CHCHNCH    6 base   150.2                           109 H        HOCH.sub.2CH.sub.2CH.sub.2                                                                 CHCHNCH    6 base   122.5                           110 phenyl   C.sub.6 H.sub.5CH.sub.2                                                                    CHCHNCH    6 HNO.sub.3                                                                            177.7                           111 H        2-thienyl-CH.sub.2                                                                         CHCHNCH    6 base   117.6                           112 H        (CH.sub.3 ).sub.3CCH.sub.2                                                                 CHCHNCH    6 HNO.sub.3                                                                            170.4                           113 4-FC.sub.6 H.sub.4                                                                     H            CHCHNCH    5 base    98.6                           114 H        (CH.sub.3).sub.2CH(CH.sub.2).sub.2                                                         CHCHNCH    6 2 HNO.sub.3                                                                          162.9                           115 H        2,3-dihydro- CHCHNCH    6 HNO.sub.3                                                                            131.1                                        1 .sub.--H-inden-1-yl                                            116 4-ClC.sub.6 H.sub.4                                                                    (CH.sub.3).sub.2CH                                                                         CHCHNCH    6 base   132.5                           117 4-ClC.sub.6 H.sub.4                                                                    cyclcohexyl  CHCHNCH    6 base   162.0                           118 3-pyridinyl                                                                            H            CHCHNCH    6 2 HCl  235.2                           119 1 .sub.--H-imidazol-                                                                   H            CHCHNCH    5 2 HCl  260.4                               1-yl                                                                      120 4-ClC.sub.6 H.sub.4                                                                    (CH.sub.3).sub.2CH(CH.sub.2).sub.2                                                         CHCHNCH    6 HCl    163.8                                                                  0.5 H.sub.2 O                          121 3-ClC.sub.6 H.sub.4                                                                    H            CHCHNCH    5 base   110.6                           122 3-FC.sub.6 H.sub.4                                                                     H            CHCHN CH   5 base   170.9                           123 4-ClC.sub.6 H.sub.4                                                                    (5-methyl-2- CHCHNCH    6 base   residue                                      furanyl)methyl                                                   124 4-ClC.sub.6 H.sub.4                                                                    H            CHCHNCH    5 base   164.9                           125 i-C.sub.3 H.sub.7                                                                      H            CHCHNCH    5 base   175.3                           126 4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5 -methyl                                                                    CHCHNCH    5 HCl/0.5 H.sub.2 O                                                                    188.6                           127 4-ClC.sub.6 H.sub.4                                                                    cyclopropyl  CHCHNCH    5 (COOH).sub.2                                                                         117                             128 CH.sub.3 C.sub.6 H.sub.5 ethyl                                                                      CHCHNCH    6 *                                      129 4-FC.sub.6 H.sub.4                                                                     H            NCHNCH     6                                        130 4-ClC.sub.6 H.sub.4                                                                    H            NCHNCH     6                                        131 2-thienyl                                                                              H            NCHNCH     6                                        132 4-FC.sub.6 H.sub.4                                                                     CH.sub.3     NCHNCH     6                                        133 3-FC.sub.6 H.sub.4                                                                     CH.sub.3     NCHNCH     6                                        134 4-CH.sub.3C.sub.6 H.sub.4                                                              CH.sub.3     NCHNCH     6                                        135 4-CH.sub.3 OC.sub.6 H.sub.4                                                            CH.sub.3     NCHNCH     6                                        136 4-ClC.sub.6 H.sub.4                                                                    CH.sub.3CH.sub.2                                                                           NCHNCH     6                                        137 4-ClC.sub.6 H.sub.4                                                                    CH.sub.3CH.sub.2CH.sub.2                                                                   NCHNCH     6                                        138 4-ClC.sub.6 H.sub.4                                                                    CH.sub.3(CH.sub.3)CH                                                                       NCHNCH     6                                        139 4-ClC.sub.6 H.sub.4                                                                    c-C.sub.6 H.sub.11                                                                         NCHNCH     6                                        140 4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5CH.sub.2                                                                    NCHNCH     6                                        141 1,2,4-tria-                                                                            CH.sub.3     NCHNCH     6                                            zol-1-yl                                                                  142 4-FC.sub.6 H.sub.4                                                                     H            CHNNCH     6                                        143 4-ClC.sub.6 H.sub.4                                                                    H            CHNNCH     6                                        144 4-FC.sub.6 H.sub.4                                                                     CH.sub.3     CHNNCH     6                                        145 4-ClC.sub.6 H.sub.4                                                                    CH.sub.3(CH.sub.3)CH                                                                       CHNNCH     6                                        __________________________________________________________________________     *(±)-2,3-dihydrobutanedioate (1:1)                                    

Example 27

To a stirred and cooled (5° C.) solution of 5.2 parts of4-[(1H-imidazol-1-yl)phenylmethyl]-1,2-benzenediamine in 4.8 parts ofacetic acid and 20 parts of water was added a solution of 1.38 parts ofsodium nitrite in 10 parts of water. The whole was stirred for 1 hour atroom temperature. The reaction mixture was treated with a sodiumhydrogen carbonate solution and the product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was crystallized from 64 parts of ethyl acetate. The product wasfiltered off and dried, yielding 4.7 parts (85.3%) of5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 178.8° C.(compound 146).

In a similar manner there were also prepared:

1-butyl-6-(1H-imidazol-1-ylmethyl)-1H-benzotriazole; mp. 49.2° C.(compound 147); and

1-butyl-5-(1H-imidazol-1-ylmethyl)-1H-benzotriazole; mp. 74.3° C.(compound 148).

Example 28

A mixture of 4.3 parts of1-[1-(4-chloro-3-nitrophenyl)ethyl]-1H-imidazole, 3.42 parts ofhydrazine monohydrate and 40 parts of 1-butanol was stirred for 12 hoursat reflux temperature. After cooling, 3.4 parts of a hydrochloric acidsolution 10N were added. The separated organic layer was evaporated. Theresidue was stirred in ethyl acetate. The product was filtered off anddried, yielding 4.5 parts (99.0%) of6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazol-1-ol monohydrochloride(compound 149).

In a similar manner there was also prepared:

    ______________________________________                                         ##STR33##                                                                    Comp.                                    mp                                   No.   R.sup.1 A.sup.1A.sup.2A.sup.3A.sup.4                                                                  P   base/salt                                                                            (°C.)                         ______________________________________                                        150   phenyl  CHCHNCH         5   base   residue                              151   H                                                                                      ##STR34##      6   base   157                                  152   H       NCHNCH          6   base   222                                  153   phenyl  NCHNCH          6   base   185                                  154   phenyl                                                                                 ##STR35##      6   base   200                                  155   phenyl                                                                                 ##STR36##      6   base   residue                              156   H       CHCHNCH         5   base   residue                              157   phenyl  CHCHNCH         6   HCl    residue                              ______________________________________                                    

Example 29

A mixture of 6.5 parts of1-[(4-fluoro-3-nitrophenyl)methyl]-1H-imidazole, 6.01 parts of hydrazinemonohydrate and 80 parts of ethanol was stirred and refluxed for 5hours. After cooling, 12 parts of a hydrochloric acid solution 5N wereadded. The whole was evaporated. The residue was stirred with 30 partsof water and the precipitated product was filtered off and boiled in 40parts of 2-propanol. 2-Propanol, saturated with hydrogen chloride, wasadded. The salt was allowed to crystallize at room temperature. It wasfiltered off and dried, yielding 4.1 parts (54.3%) of6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol- 1-ol-monohydrochloride; mp.207.4° C. (compound 158).

In a similar manner there were also prepared:

6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzotriazol-1-ol(compound 159).

Example 30

A mixture of 3.2 parts of6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol, 1 part of potassiumcarbonate and 27 parts of N,N-dimethylformamide was stirred for 30minutes at room temperature. 2.1 Parts of1-(chloromethyl)-3-methylbenzene were added and stirring was continuedfor 3 hours at room temperature. The mixture was allowed to standovernight at room temperature and was evaporated. The residue wasdiluted with water and the product was extracted with dichloromethane.The extract was dried, filtered and concentrated. The concentrate waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The solidresidue was crystallized from a mixture of ethyl acetate and2,2'-oxybispropane (10:20 by volume). The product was filtered off,washed with 2,2'-oxybispropane and dried, yielding 3.4 parts (70.9%) of6-(1H-imidazol-1-ylmethyl)-1-[(3-methylphenyl)methoxy]-1H-benzotriazole;mp. 120.1° C. (compound 160). In a similar manner there were alsoprepared:

    __________________________________________________________________________     ##STR37##                                                                    Comp.                                                                         No. R.sup.1                                                                           R.sup.2-b     A.sup.1A.sup.2A.sup.3A.sup.4                                                              base/salt                                                                           mp (°C.)                       __________________________________________________________________________    161 H   CH.sub.3CH.sub.2                                                                            CHCHNCH     base  108.5                                 162 H   2-CH.sub.3C.sub.6 H.sub.4CH.sub.2                                                           CHCHNCH     base  134.6                                 163 H   4-CH.sub.3C.sub.6 H.sub.4CH.sub.2                                                           CHCHNCH     base  109.4                                 164 H   2-FC.sub.6 H.sub.4CH.sub.2                                                                  CHCHNCH     base  105.8                                 165 H   C.sub.6 H.sub.5O(CH.sub.2).sub.3                                                            CHCHNCH     (COOH).sub.2                                                                        154.1                                  166*                                                                             H   C.sub.6 H.sub.5CH CHCH.sub.2                                                                CHCHNCH     (COOH).sub.2                                                                        102.2                                 167 H   C.sub.6 H.sub.5OCH.sub.2CH.sub.2                                                            CHCHNCH     base  124.1                                 168 H   3-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                         CHCHNCH     base  118.9                                 169 H   4-FC.sub.6 H.sub.4CH.sub.2                                                                  CHCHNCH     base  126.2                                 170 H   3-FC.sub.6 H.sub.4CH.sub.2                                                                  CHCHNCH     base  114.4                                 171 H   (C.sub.6 H.sub.5).sub.2CH                                                                   CHCHNCH     (COOH).sub.2                                                                        163.4                                 172 H   2-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                         CHCHNCH     base  127.2                                 173 H   4-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                         CHCHNCH     base   92.6                                 174 H   2-thienyl-CH.sub.2                                                                          CHCHNCH     base  126.5                                 175 H   (CH.sub.3).sub.2NCH.sub.2CH.sub.2                                                           CHCHNCH     2HCl  230.1                                 176 H   C.sub.6 H.sub.5SCH.sub. 2                                                                   CHCHNCH     base  118.0                                 177 H   1-naphthalenyl-CH.sub.2                                                                     CHCHNCH     base  158.0                                 178 H   HOCH.sub.2CH.sub.2CH.sub.2                                                                  CHCHNCH     base  137.0                                 179 H   CHCCH.sub.2   CHCHNCH     base  130.0                                 180 H   F.sub.3 CCH.sub.2                                                                           CHCHNCH     base   91.7                                 181 H   C.sub.6 H.sub.4SCH.sub.2CH.sub.2                                                            CHCHNCH     base   84.2                                 182 H   2-pyrimidinyl CHCHNCH     base  167.7                                 183 H   cyclo-C.sub.3 H.sub.5CH.sub.2                                                               CHCHNCH     HNO.sub.3                                                                           136.5                                 184 H   cyclo-C.sub.6 H.sub.11CH.sub.2                                                              CHCHNCH     HNO.sub.3                                                                           149.0                                 185 H   CH.sub.3CH.sub.2                                                                             ##STR38##  base   93.6                                 186 H   CH.sub.3CH.sub.2                                                                            NCHNCH      base  116.9                                 187 H   CH.sub.3CH.sub.2CH.sub.2CH.sub.2                                                             ##STR39##  HNO.sub.3                                                                            95.1                                 188 phenyl                                                                            C.sub.6 H.sub.5CH.sub.2                                                                     CHCHNCH     (COOH).sub.2                                                                        152.5                                 189 phenyl                                                                            C.sub.6 H.sub.5CH.sub.2                                                                     CHCHNCH     base  113.2                                 190 H                                                                                  ##STR40##    CHCHNCH     base  210.3                                 191 H   C.sub.6 H.sub.5C.sub.6 H.sub.4CH.sub.2                                                      CHCHNCH     base  133.0                                 192 H   (1 .sub.--H-benzimidazol-                                                                   CHCHNCH     base  212.5                                         2-yl)methyl                                                           193 H   (2-methyl-1 .sub.--H-benzi-                                                                 CHCHNCH     base  209.1                                         midazol-5-yl)methyl                                                   194 H   (2,3-dihydro-1,4-                                                                           CHCHNCH     (COOH).sub.2                                                                        171.6                                         benzodioxin-2-yl)methyl                                               __________________________________________________________________________     * = Eform                                                                

Example 31

A mixture of 3.23 parts of6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol, 2.07 parts of potassiumcarbonate and 20 parts of dimethyl sulfoxide was stirred for 10 minutesat room temperature. Then there were added 2.55 parts of 2-iodopropaneand stirring was continued first for 15 minutes at room temperature andthen for 1 hour at 50° C. The reaction mixture was evaporated. 50 Partsof water were added. The product was extracted with dichloromethane. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from 14 parts of 1,1'-oxybisethane. The product wasfiltered off and dried, yielding 3.3 parts (85.5%) of6-(1H-imidazol-1-ylmethyl)-1-(1-methylethoxy)-1H-benzotriazole; mp.114.3° C. (compound 195).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR41##                                                                    Comp.                                                                         No. R.sup.1                                                                           R.sup.2-b         A.sup.1A.sup.2A.sup.3A.sup.4                                                              base/salt                                                                            mp (°C.)                  __________________________________________________________________________    196 H   3-pyridinyl-CH.sub.2                                                                            CHCHNCH     base   120.6                            197 H   CH.sub.3CH.sub.2(CH.sub.3)CH                                                                    CHCHNCH     HNO.sub.3                                                                            133.3                            198 H   CH.sub.3CH.sub.2OC(O)CH.sub.2                                                                   CHCHNCH     HNO.sub.3                                                                            143.3                            199 H   CH.sub.3CH.sub.2OC(O)(CH.sub.2).sub.4                                                           CHCHNCH     base   oil                              200 H   CH.sub.3CH.sub.2OC(O)(CH.sub.2).sub.3                                                           CHCHNCH     base   oil                              201 H   CH.sub. 3(CH.sub.2).sub.4                                                                       CHCHNCH     HNO.sub.3                                                                            115.2                            202 H   CH.sub.3(CH.sub.2).sub.5                                                                        CHCHNCH     HNO.sub.3                                                                             93.9                            203 H   CH.sub.3(CH.sub.2).sub.8                                                                        CHCHNCH     HNO.sub.3                                                                             90.0                            204 H   Br(CH.sub.2).sub.2                                                                              CHCHNCH     HNO.sub.3                                                                            131.3                            205 H   2-pyridinyl-CH.sub.2                                                                            CHCHNCH     base    81.7                            206 H   CH.sub.3(CH.sub.2).sub.6                                                                        CHCHNCH     HNO.sub.3                                                                             80.7                            207 H   C.sub.6 H.sub.5(CH.sub.2).sub.3                                                                 CHCHNCH     (COOH).sub.2                                                                         135.7                            208 H   C.sub.6 H.sub.5(CH.sub.2).sub.2                                                                 CHCHNCH     (COOH).sub.2                                                                         136.0                            209 H   1-methyl-4-piperidinyl                                                                          CHCHNCH     2HNO.sub.3                                                                           176.9                            210 CH.sub.3                                                                          CH.sub.3CH.sub.2OC(O)CH.sub.2                                                                   CHCHNCH     base   residue                          211 phenyl                                                                            CH.sub.3CH.sub.2  NCHNCH      0.5(COOH).sub.2                                                                       92.1                            212 phenyl                                                                            CH.sub.3CH.sub.2                                                                                 ##STR42##  HNO.sub.3                                                                            125.8                            213 phenyl                                                                            C.sub.6 H.sub.5CH.sub.2                                                                          ##STR43##  base   156.2                            214 phenyl                                                                            CH.sub.3CH.sub.2CH.sub.2CH.sub.2                                                                 ##STR44##  HNO.sub.3                                                                            126.9                            __________________________________________________________________________

Example 32

A mixture of 4.5 parts of6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazol-1-ol monohydrochloride,3.12 parts of iodoethane, 3.7 parts of sodium carbonate and 63 parts ofN,N-dimethylformamide was stirred for 4 hours at room temperature. Thereaction mixture was evaporated and the residue was taken up in water.The product was extracted with methylbenzene. The extract was dried,filtered and evaporated. The residue was crystallized from a mixture of27 parts of ethyl acetate and 21 parts of 2,2'-oxybispropane. Theproduct was filtered off and dried, yielding 2.26 parts (51.6%) of1-ethoxy-6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazole; mp. 81.1° C.(compound 215).

In a similar manner there were also prepared:

5-[(1H-imidazol-1-yl)phenylmethyl]-1-(1-methylethoxy)-1H-benzotriazole;mp. 85.7° C. (compound 216);

1-ethoxy-5-[(1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 85.5°C. (compound 217);

6-[1-(1H-imidazol-1-yl)ethyl]-1-(phenylmethoxy)-1H-benzotriazole; mp.128.6° C. (compound 218); and

6-[1-[(1H-imidazol-1-yl)ethyl]-1-(2-methoxyethoxy)-1H-benzotriazole(±)-2,3-dihydroxybutanedioate; mp. 140.0° C. (compound 219).

Example 33

To a stirred and heated (50° C.) mixture of 2.81 parts of6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol and 22.5 parts ofN,N-dimethylformamide were added 0.69 parts of a sodium hydridedispersion. The reaction mixture was stirred until hydrogen evolutionhad ceased. 1.28 Parts of 1-chloro-2-methoxyethane were added at roomtemperature and stirring was continued for a while. 22 Parts of dimethylsulfoxide and 0.04 parts of2-(2-methoxyethoxy)-N,N-bis[2-(2-methoxyethoxy)ethyl]ethanamine wereadded. The reaction mixture was stirred overnight at 50° C. and thenpoured into water. The product was extracted with dichloromethane. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from a mixture of ethyl acetate and 2,2'-oxybispropane (1:3by volume). The product was filtered off, washed with a mixture of ethylacetate and 2,2'-oxybispropane (1:3 by volume) and 2,2'-oxybispropaneand dried in vacuo at 50° C., yielding 1.66 parts (46.7%) of6-(1H-imidazol-1-ylmethyl)-1-(2-methoxyethoxy)-1H-benzotriazole; mp.77.0° C. (compound 220).

Example ÷

To a stirred mixture of 4.5 parts of5-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol and 94 parts ofN,N-dimethylformamide was added portionwise 1 part of a sodium hydridedispersion 50%. Upon complete addition, stirring was continued tillhydrogen evolution had ceased. 1.3 Parts of iodomethane were added atonce and stirring was continued at room temperature. TheN,N-dimethylformamide formamide layer was evaporated and the residue wastaken up in water and a mixture of trichloromethane, methanol andmethanol, saturated with ammonia (90:5:5 by volume). The product wasextracted with a mixture of trichloromethane, methanol and methanol,saturated with ammonia (90:5:5 by volume). The extract was dried,filtered and evaporated. The residue was purified by columnchromatography over silica gel first using trichloromethane and then amixture of trichloromethane and methanol (90:10 by volume) as eluents.The pure fractions were collected and the eluent was evaporated. Theresidue was stirred in 2,2'-oxybispropane. The product was filtered offand dried in vacuo at 50° C., yielding 3.1 parts (64.3%) of5-(1H-imidazol-1-ylmethyl)-1-methoxy-1H-benzotriazole; mp. 94.3° C.(compound 221).

In a similar manner there was also prepared:

5-(1H-imidazol-1-ylmethyl)-1-(phenylmethoxy)-1H-benzotriazole; mp.113.7° C. (compound 222);

6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1-(phenylmethoxy)-1H-benzotriazoleethanedioate(2:3); mp. 169.3° C. (compound 223); and

1-butoxy-6-[(3-chlorophenyl) (1H-imidazol-1-yl)methyl]-1H-benzotriazoleethanedioate (1:1); mp. 96.5° C. (compound 224).

Example 35

To a stirred solution of 0.46 parts of sodium in 24 parts of methanolwere added 4.3 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol.The mixture was stirred for 10 minutes and then evaporated. 9 Parts ofmethylbenzene were added to the residue and the whole was evaporatedagain. To the residue in 9 parts of N,N-dimethylformamide was added asolution of 3.12 parts of iodoethane in 4.5 parts ofN,N-dimethylformamide. The whole was stirred for 1 hour at 50° C. andevaporated. 60 Parts of water were added and the product was extractedwith dichloromethane. The extract was dried, filtered and evaporated.The residue was purified by column chromatography over silica gel usinga mixture of trichloromethane and methanol (95:5 by volume) as eluent.The pure fractions were collected and the eluent was evaporated. Theresidue was converted into the hydrochloride salt in 2-propanol and4-methyl-2-pentanone. The salt was filtered off and dried, yielding 4.5parts (80%) of 1-ethoxy-6-(1H-imidazol-1-ylmethyl)-1H-benzotriazolemonohydrochloride; mp. 140.2° C. (compound 225).

In a similar manner there were also prepared:

1-butoxy-6-(1H-imidazol-1-ylmethyl)-1H-benzotriazole monohydrochloride;mp. 124.2° C. (compound 226);

6-(1H-imidazol-1-ylmethyl)-1-propoxy-1H-benzotriazole monohydrochloride.hemihydrate; mp. 130.5° C. (compound 227); and

6-(1H-imidazol-1-ylmethyl)-1-(phenylmethoxy)-1H-benzotriazole; mp.113.8° C. (compound 228).

Example 36

To a stirred suspension of 4.7 parts of6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol in 60 parts of ethanolwere added 22.5 parts of a sodium hydroxide solution 1N. The whole wasstirred till a clear solution was obtained. The mixture was evaporatedto dry. The residue was dissolved in 18 parts of N,N-dimethylformamide.To the thus obtained solution was added at once a solution of 3.2 partsof iodomethane in 9 parts of N,N-dimethylformamide. After stirring for30 minutes at room temperature, the whole was evaporated. The residuewas purified by column chromatography over silica gel using a mixture oftrichloromethane and methanol (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from 8 parts of 4-methyl-2-pentanone. The product wasfiltered off and dried, yielding 3.3 parts (65.4%) of6-(1H-imidazol-1-ylmethyl)-1-methoxy-1H-benzotriazole; mp. 132.4° C.(compound 229).

Example 37

A mixture of 5.85 parts of6-[phenyl(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazol-1-ol, 1.4 partsof potassium carbonate and 27.5 parts of dimethyl sulfoxide was stirredfor 30 minutes at 50° C. After cooling, 3.55 parts of ethyl2-bromoacetate were added and the whole was stirred for 2 hours at roomtemperature. Another portion of 1.4 parts of potassium carbonate wasadded. After stirring for 3 hours at 50° C., the mixture was cooled and2.0 parts of concentrated hydrochloric acid were added. The dimethylsulfoxide layer was evaporated. The residue was taken up in 25 parts ofwater and 130 parts of dichloromethane. The separated organic layer wasdried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane,methanol and methanol, saturated with ammonia, (92:4:4 by volume) aseluent. The pure fractions were collected and the eluent was evaporated.The residue was crystallized from 20 parts of 4-methyl-2-pentanone. Theproduct was filtered off and dried, yielding 4.4 parts (79.6%) of5-[phenyl(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazole; mp. 182.7° C.(compound 230).

In a similar manner there were also prepared:

5-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazole; mp. 165.3° C. (compound231);

5-[(2-methyl-1H-imidazol-1-yl)methyl]-1H-benzotriazole; mp. 214.3° C.(compound 232); and

5-[(4-methyl-1H-imidazol-1-yl)phenylmethyl]-1H-benzotriazole; mp. 166.7°C. (compound 233).

Example 38

A mixture of 4.3 parts of6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol monohydrochloride and120 parts of methanol was hydrogenated at normal pressure and at 50° C.with 2 parts of platinium-on-charcoal catalyst 5%. After the calculatedamount of hydrogen was taken up, the catalyst was filtered off and thefiltrate was evaporated. The residue was crystallized twice fromethanol. The product was filtered off and dried, yielding 2.9 parts(72%) of 5-(1H-imidazol-1-ylmethyl)-1H-benzotriazole monohydrochloride;mp. 230.4° C. (compound 234).

Example 39

2.47 Parts of 5-(1H-imidazol-1-ylmethyl)-1H-benzotriazole were addedportionwise to 30 parts of fuming nitric acid while stirring. Uponcomplete addition, stirring was continued overnight at room temperature.The reaction mixture was poured into 100 parts of crushed ice andnitrogen was bubbled through the mixture during 30 minutes. Theprecipitated product was filtered off, washed with water and purified byreversed phase chromatography (HPLC) over Li Chroprep RP 18 using amixture of methanol, acetonitrile and an ammonium acetate solution 0.5%(17:8:75 by volume) as eluent. The desired fraction was collected andthe eluent was evaporated. The residue was stirred in methanol and2,2'-oxybispropane. The precipitated product was filtered off and boiledin methanol. The product was filtered off, washed with methanol and2,2'-oxybispropane and dried in vacuo at 50°-60° C., yielding 0.05 parts(1.6%) of 5-(1H-imidazol-1-ylmethyl)-6-nitro-1H-benzotriazole; mp.286.0° C. (decomp.) (compound 235).

Example 40

A mixture of 3.2 parts of ethyl4-[[6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-yl]oxy]butanoate, 25parts of a sodium hydroxide solution 1N and 20 parts of ethanol wasstirred for 1.5 hours at room temperature. 25 Parts of a hydrochloricacid solution 1N were added and the whole was concentrated to a volumeof about 20 parts. The precipitated product, which was formed duringconcentration, was filtered off, washed with water, 2-propanol and1,1'-oxybisethane and dried, yielding 2.1 parts (71%) of4-[[6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-yl]oxy]butanoic acid;mp. 170.5° C. (compound 236).

In a similar manner there was also prepared:

5-[[6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-yl]oxy]pentanoic acid;mp. 132.7° C. (compound 237).

Example 41

A solution of 7.1 parts of6-[[4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)phenyl](1H-imidazol-1-yl)methyl]-1-methyl-1H-benzotriazolein 100 parts of a hydrochloric acid solution 3N was stirred overnight atreflux temperature. The reaction mixture was evaporated to dry, yielding8.9 parts (100%) of4-[(1H-imidazol-1-yl)(1-methyl-1H-benzotriazol-6-yl)methyl]benzoic acidmonohydrochloride as a residue (compound 238).

Example 42

A solution of 8.9 parts of4-[(1H-imidazol-1-yl)(1-methyl-1H-benzotriazol-6-yl)methyl]benzoic acidmonohydrochloride in 32.4 parts of thionyl chloride was stirred for 1hour at room temperature. The reaction mixture was evaporated. Asolution of the residue in 80 parts of ethanol was stirred for 1 hour at60° C. The reaction mixture was concentrated. The concentrate was takenup in a diluted potassium carbonate solution and the product wasextracted with dichloromethane. The extract was dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of dichloromethane and methanol (98:2 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was converted into the ethanedioate salt. Thesalt was filtered off and dried, yielding 1 part (8.5%) of ethyl4-[(1H-imidazol-1-yl)(1-methyl-1H-benzotriazol-6-yl)methyl]benzoateethanedioate(1:1); mp. 155.5° C. (compound 239).

Example 43

A mixture of 7 parts of5-[1(1H-imidazol-1-yl)-2-butynyl]-1-methyl-1H-benzotriazole, 0.1 partsof quinoline, 54 parts of ethyl acetate and 32 parts of ethanol washydrogenated at 931.00 Pa and at room temperature with 0.3 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off over diatomaceousearth and the filtrate was evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture of dichloromethaneand methanol (95:5 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom a mixture of dichloromethane and 1,1'-oxybisethane. The product wasfiltered off and dried, yielding 1.4 parts (19.7%) of5-[1-(1H-imidazol-1-yl)-2-butenyl]-1-methyl-1H-benzotriazole; mp. 104°C. (compound 240).

Example 44

A mixture of 2.6 parts of4-[(1H-imidazol-1-yl)(1-methyl-1H-benzotriazol-5-yl)methyl]benzaldehyde,0.85 parts of hydroxylamine monohydrochloride, 16 parts of ethanol and3.4 parts of potassium carbonate was stirred for 1 hour at 50° C. Thereaction mixture was filtered and the filtrate was evaporated. Theresidue was purified by column chromatography over silica gel using amixture of trichloromethane and methanol (95:5 by volume) as eluent. Thepure fractions were collected and the eluent was evaporated. The residuewas crystallized from 2-propanone. The product was filtered off anddried, yielding 1.7 parts (63.9%) of4-[(1H-imidazol-1-yl)(1-methyl-1H-benzotriazol-5-yl)methyl]benzaldehyde,oxime; mp. 149.5° C. (compound 241).

C. Pharmacological Examples

The useful inhibition of the aromatase activity of the compounds offormula (I) can be demonstrated in the following test procedures.

Example 45: In Vitro-Inhibition of the Aromatase Activity Test

For example, one may study the effect of the compounds of the presentinvention on the conversion of 1,2[3H]androstenedione into estrone andestradiol in the presence of human placental microsomes followingprocedures analogous to those described in J. Steroid Biochem., 7, 787(1976).

Human placental microsomes were diluted in potassium phosphate buffer(0.1M, pH 7.4) to give about 50% conversion of androgens to estrogens(protein content: about 0.5 mg). Four ml human placental microsomes wereincubated in a final volume of 5 ml with 0.2 μCil,2[3H]-androstenedione, 2 μg androstendione and 5 μl of test compoundand/or dimethyl sulfoxide (DMSO). Further the incubation mixturecontained a NADPH-regenerating system consisting of ATP (2,48 mM), NADP(0.97 mM), glucose-6-phosphate (8.22 mM), glucose-6-phosphatedehydrogenase (0.98 units) and MgCl₂ (2.46 mM). The reaction wasinitiated by the addition of androstenedione and proceeded for 30 min at37° C. During the incubation period, the mixtures were gassed with air.In this assay, aromatization of androstenedione results in theproduction of [3H]-H₂ O which is isolated by extracting the samples withchloroform to remove the free steroid. Samples are counted in a liquidscintillation spectrometer and the percent inhibition is determined bycomparing the results with control samples incubated without inhibitor.

The effects of the compounds of the present invention are presented intable I, column (a) as the concentration in μM of the compound requiredto obtain 50% inhibition of the estrogen synthesis (IC₅₀ -values).

Example 46: In Vivo-Inhibition of the Aromatase Activity

Immature female Wistar rats weighing 120 g were injected subcutaneouslywith 200 I.U. of pregnant mare's serum gonadotropin (PMSG). Ninety hourslater, 1 mg/kg of the test compound dissolved in 0.5 ml 20%polyethyleneglycol in water was administered by oral gavage. Controlanimals received 20% polyethyleneglycol only. Two hours following drugor placebo administration the rats were killed by decapitation and trunkblood was collected on heparine. Plasma estradiol concentrations weremeasured by standard radio-immunological procedures. The percentagerecovery estradiol relative to the controls are depicted in column (b)of table (I). The results in this table are not given for the purpose oflimiting the invention thereto but only to exemplify the usefulpharmacological properties of all the compounds within the scope offormula (I).

    ______________________________________                                        Compound   IC.sub.50 -values (μM)                                                                  % recovery estradiol                                  ______________________________________                                        225        0.0100       19                                                    226        0.0067       19                                                    227        0.0074       19                                                    228        0.0052       -                                                     195        0.0120       19                                                    196        0.0110       --                                                    197        0.0110       --                                                    198        0.0180       --                                                    201        0.0067       19                                                    202        0.0071       21                                                    203        0.0170       --                                                    204        0.0092       19                                                    206        0.0080       --                                                     2         0.0160       20                                                     4         0.0160       --                                                     6         0.0120       --                                                    207        0.0073       26                                                    208        0.0110       --                                                     7         0.0257        7                                                    147        0.0076       21                                                    176        0.0120       --                                                    191        0.0234       --                                                    179        0.0232       --                                                     75        0.0242       27                                                     76        0.0347        9                                                     87        0.0269        5                                                     89        0.0150        5                                                     90        0.0227        5                                                     91        0.0088       --                                                     92        0.0087       15                                                     15        0.0226        2                                                     93        0.0105        8                                                     17        0.0182        7                                                     97        0.0131       10                                                     99        0.0178       11                                                     23        0.0075       --                                                    100        0.0143        3                                                    101        0.0174        7                                                    102        0.0317        2                                                    103        0.0163        5                                                     28        0.0253        6                                                     29        0.0159        7                                                     30        0.0222        7                                                     31        0.0342        8                                                    104        0.0206        9                                                     33        0.0246        5                                                    105        0.0198       14                                                    213        0.0362       --                                                    106        0.0244        8                                                    107        0.0141        6                                                    108        0.0152        3                                                    109        0.0262       --                                                    188        0.0182       --                                                    111        0.0143       19                                                    113        0.0188        4                                                     48        0.0166        6                                                     50        0.0183        1                                                     51        0.0222        7                                                    115        0.0144       22                                                     55        0.0188        3                                                     56        0.0215        8                                                    116        0.0249       20                                                     64        0.0257        3                                                    117        0.0125        9                                                     69        0.0290        5                                                     77        0.0176       21                                                    220        0.0200       --                                                    120        0.0089       --                                                     59        0.0180       --                                                    ______________________________________                                    

D) Composition Examples

The following formulations exemplify typical pharmaceutical compositionsin dosage unit form suitable for systemic administration to animal andhuman subjects in accordance with the instant invention. "Activeingredient" (A.I.) as used throughout these examples relates to acompound of formula (I) or a pharmaceutically acceptable acid additionsalt thereof.

Example 47: Oral Drops

500 Grams of the A.I. was dissolved in 0.5 liters of 2-hydroxypropanoicacid and 1.5 liters of the polyethylene glycol at 60°˜80° C. Aftercooling to 30°˜40° C. there were added 35 liters of polyethylene glycoland the mixture was stirred well. Then there was added a solution of1750 grams of sodium saccharin in 2.5 liters of purified water and whilestirring there were added 2.5 liters of cocoa flavor and polyethyleneglycol q.s. to a volume of 50 liters, providing an oral drop solutioncomprising 10 milligrams of the A.I. per milliliter. The resultingsolution was filled into suitable containers.

Example 48: Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 liters of boiling purified water.In 3 liters of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 liters 1,2,3-propanetriol and 3 liters of sorbitol 70%solution were added thereto. 40 Grams of sodium saccharin were dissolvedin 0.5 liters of water and 2 milliliters of raspberry and 2 millilitersof gooseberry essence were added. The latter solution was combined withthe former, water was added q.s. to a volume of 20 liters providing anoral solution comprising 20 milligrams of the active ingredient perteaspoonful (5 milliliters). The resulting solution was filled insuitable containers.

Example 49: Capsules

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatingcapsules, comprising each 20 milligrams of the active ingredient.

Example 50: Film-Coated Tablets Preparation of Tablet Core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone(Kollidon-K 90®) in about 200 milliliters of water. The wet powdermixture was sieved, dried and sieved again. Then there was added 100grams microcrystalline cellulose (Avicel®) and 15 grams hydrogenatedvegetable oil (Sterotex®). The whole was mixed well and compressed intotablets, giving 10.000 tablets, each containing 10 milligrams of theactive ingredient.

Coating

To a solution of 10 grams methyl cellulose (Methocel 60 HG®) in 75milliliters of denaturated ethanol there was added a solution of 5 gramsof ethyl cellulose (Ethocel 22 cps®) in 150 milliliters ofdichloromethane. Then there were added 75 milliliters of dichloromethaneand 2.5 milliliters 1,2,3-propanetriol. 10 Grams of polyethylene glycolwas molten and dissolved in 75 milliliters of dichloromethane. Thelatter solution was added to the former and then there were added 2.5grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30milliliters of concentrated colour suspension (Opaspray K-1-2109®) andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

Example 51: Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 liters of boiling waterfor injection. After cooling to about 50° C. there were added whilestirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams ofthe A.I.. The solution was cooled to room temperature and supplementedwith water for injection q.s. ad 1 liter volume, giving a solution of 4milligrams A.I. per milliliters. The solution was sterilized byfiltration (U.S.P. XVII p. 811) and filled in sterile containers.

Example 52: Suppositories

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 milliliters polyethylene glycol 400.12 Grams surfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad300 grams were molten together. The latter mixture was mixed well withthe former solution. The thus obtained mixture was poured into moulds ata temperature of 37°˜38° C. to form 100 suppositories each containing 30milligrams of the active ingredient.

We claim:
 1. A compound of the formula: ##STR45## a pharmaceuticallyacceptable acid addition salt or a stereochemically isomeric formthereof, wherein:--A¹ ═A² --A³ ═A⁴ -- represents a bivalent group of theformula:

    --CH═N--CH═CH--                                    (a-1),

    --CH═N--CH═N--                                     (a-2),

    or

    --CH═N--N═CH--                                     (a-3);

R represents hydrogen or C₁₋₆ alkyl; R¹ represents hydrogen, C₁₋₆ alkyloptionally substituted with phenyl or substituted phenyl, phenyl,substituted phenyl, C₃₋₇ cycloalkyl, pyridinyl, naphthalenyl, thienyl,furanyl, imidazolyl, triazolyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; R²represents pyrimidinyloxy; and R³ represents hydrogen or nitro,whereinsubstituted phenyl is phenyl substituted with up to three substituentseach independently selected from the group consisting of halo, hydroxy,hydroxymethyl, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkyloxycarbonyl, carboxyl, formyl, (hydroxyimino)methyl, nitrile,amino, mono-- and di(C₁₋₆ alkyl) amino, and nitro.
 2. The compound ofclaim 1 wherein the ##STR46## moiety is substituted on either the 5 or 6position of the benzotriazole ring.
 3. The pharmaceutical composition ofclaim 1 wherein the ##STR47## moiety is substituted on either the 5 or 6position of the benzotriazole ring.
 4. The compound of claim 1 whereinsaid compound is 6-(1H-imidazol-1-ylmethyl)-1-(2-pyrimidinyloxy)-1H-benzotriazole.
 5. A pharmaceuticalcomposition comprising an inert carrier and as active ingredient anestrogene hormone biosynthesis inhibitory amount of a compound of theformula: ##STR48## a pharmaceutically acceptable acid addition salt or astereochemically isomeric form thereof, wherein:--A¹ ═A² --A³ ═A⁴ --represents a bivalent group of the formula:

    --CH═N--CH═CH--                                    (a-1),

    --CH═N--CH═N--                                     (a-2),

    or

    --CH═N--N═CH--                                     (a-3);

R represents hydrogen or C₁₋₆ alkyl; R¹ represents hydrogen, C₁₋₆ alkyloptionally substituted with phenyl or substituted phenyl, phenyl,substituted phenyl, C₃₋₇ cycloalkyl, pyridinyl, naphthalenyl, thienyl,furanyl, imidazolyl, triazolyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; R²represents pyrimidinyloxy; and R³ represents hydrogen or nitro,whereinsubstituted phenyl is phenyl substituted with up to three substituentseach independently selected from the group consisting of halo, hydroxy,hydroxymethyl, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆alkyloxycarbonyl, carboxyl, formyl, (hydroxyimino)methyl, nitrile,amino, mono- and di(C₁₋₆ alkyl)amino, and nitro.
 6. The pharmaceuticalcomposition of claim 5 wherein said compound is6-(1H-imidazol-1-ylmethyl)-1-(2-pyrimidinyloxy)-1H-benzotriazole.